First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis, Rheumatoid
Intervention: Placebo; GSK3358699; GM-CSF; LPS; Cantharidin
Intervention description: Placebo will be administered as a matching oral solution or matching capsule to study drug GSK3358699, during Part A and C once daily; GSK3358699, will be administered from 1 mg to 45 mg as an oral solution (1 to 10 mg) or as a capsule (3 to 45 mg), in Part A, B and Part C once daily.; The GM-CSF will be administered as an intravenous infusion to subjects as 60 microgram per meter^2 in Part A (Day 1) and Part C (Day 14).This will be administered for 2 hours approximately, no later than 24 hours post -dose of the GSK3358699 or placebo in Part C; LPS will be administered as an intravenous injection to subjects not exceeding 0.75 nanogram per kilogram in Part A (Day 1) and Part C (Day 14). This will be administered no later than 24 hours post -dose of the GSK3358699 or placebo in Part C.; This will be applied as a topical application with 0.7% cantharidin liquid which will be diluted with acetone to 0.2%.
Intervention MeSH terms: Cantharidin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Study will be conducted as Part A, B and C. Part A will consist of 2-interlocking cohorts, where each subject will receive maximum 2-single ascending oral doses of GSK3358699 and 1 dose of placebo, in Treatment Periods (TP) 1 to 3. In TP 4 subjects will receive GSK3358699, dose evaluated in TP (1 to 3) or placebo, with cantharidin induced blisters and either LPS or GM-CSF in vivo challenge. Part B will comprise of single cohort taking part in two-way cross over, with open label phase where each subject will receive single oral dose of GSK3358699 (based on Part A), under fed and fasted conditions in each TP. Part C will consist of 3 cohorts with multiple ascending doses, with every cohort having one repeat dose TP with 14 days of daily dosing of either GSK3358699 or placebo. Subjects on Day 14 will receive cantharidin induced blisters with either LPS or GM-CSF in vivo challenge. An optional, cohort 7 may be included for further dose evaluation of GSK3358699 or alternate dosing schedule.
Masking: Double (Participant, Investigator)
Masking description: This will be a double blind (sponsor open) study with respect to allocation of GSK3358699 or placebo to subjects. All site staff will be blinded with the exception of un-blinded pharmacists. Investigators will be un-blinded with respect to the LPS and GM-CSF allocation. The food effect part of the study (Part B) will be open-label
Enrollment: 48.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the
      subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate
      the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and
      fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a
      pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also
      intends to understand the effect of GSK3358699 on systemic markers of inflammation following
      low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor
      (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been
      carefully designed to explore the in vivo biology of the target and the potential for the
      study drug to become a transformative medicine for subjects in multiple immuno-inflammatory
      disease indications.
    

Eligibility criteria:

        Inclusion Criteria: - Subjects enrolled into the study, where they will be administered LPS
        or GM-CSF challenge, must be 18 to 55 years of age inclusive, at the time of signing the
        informed consent. Subjects enrolled into the study where they will not be administered LPS
        or GM-CSF challenge must be 18 to 65 years of age inclusive, at the time of signing the
        informed consent. - Subjects must be overtly healthy as determined by medical evaluation
        including medical history, physical examination, laboratory tests and cardiac monitoring. -
        Body weight must be > = 50 kilogram (kg) and body mass index (BMI) within the range
        18.5-35.0 kg per square meter (kg/m^2) (inclusive). - Male subjects agreeing to use
        contraceptive methods during the treatment Period and for at least 91 days, after the last
        dose of study treatment and refrain from donating sperm during this Period. - Capable of
        giving informed consent. Exclusion Criteria: - Current or chronic history of pancreatitis,
        diabetes mellitus or impaired glucose tolerance, gastrointestinal disease, 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 [Sampson et al 2006], cardiac disease including clinically significant
        ventricular arrhythmias or long QT syndrome, renal disease where clinically significant
        (minor abnormalities may be permitted base on discussion between investigator and medical
        monitor), respiratory disease or conditions including but not limited to asthma, chronic
        obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory
        infection (childhood asthma is not an exclusion criterion), 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; frequent vasovagal syncope, surgery
        requiring general anaesthetic or significant trauma in 3 months leading to study enrolment,
        relevant skin conditions (e.g. recent history of 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,
        coagulation disorders, peripheral edema, lymphangitis, lymphedema, pleural or pericardial
        effusion, hemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder. -
        History of malignancies e.g. recurrent basal cell carcinoma, hematological malignancy. -
        For subjects receiving cantharidin: Presence on either forearm of tattoos, naevi,
        hypertrophic scars, keloids, hyper- or hypo- pigmentation that may, in the opinion of the
        Investigator, interfere with study assessments. 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. - Family history of premature
        cardiovascular disease or long QT syndrome. - QT interval with Fridericia's correction
        (QTcF) > 450 millisecond (msec), based on averaged QTcF values of triplicate ECGs obtained
        over a brief recording period. - Unable or unwilling to refrain from taking prescription or
        non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days
        (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is
        longer) before the start of study treatment until completion of the follow-up visit.
        Paracetamol, at a dose of <= 2 grams per day was permitted for use anytime during the
        study. Other concomitant medications will be considered on case by case basis. - The
        subjects have participated in a clinical trial and received an investigational product
        within the following time period prior to the first dosing day in the study: 30 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. - Exposure to
        more than four new chemical entities within 12 months prior to the first dosing day. -
        Previous exposure to intravenous lipopolysaccharide (LPS) in a clinical research setting. -
        Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) at screening. - Bilirubin
        >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
        bilirubin <35%) at screening. - Presence of hepatitis B surface antigen (HBsAg), positive
        hepatitis C antibody test result at screening or within 3 months prior to first dose of
        study treatment. - A positive pre-study drug/alcohol screen at screening. - A positive test
        for human immunodeficiency virus (HIV) antibody at screening. - Persistent clinically
        significant abnormal C-reactive protein (CRP) levels at screening - Persistent clinically
        significant abnormal white cell count (WCC) levels at screening (if clinically significant
        abnormality is detected, WCC can be retested as clinically indicated) - Platelets < 150 x
        10^9 per liter (L) at screening. - Fasted Triglycerides >3.4 millimole per liter (mmol/L)
        at screening. - Fasted Total cholesterol >7.7 mmol/L at screening. - Random glucose > =
        11.1 mmol/L at screening. - Urinary cotinine levels indicative of smoking or history or
        regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
        - History of regular alcohol consumption within 6 months of the study defined as: an
        average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a
        half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25
        mL). - Where participation in the study would result in donation of blood or blood products
        in excess of 500 mL within a 56 day period. - Unable to comply with precautions to minimize
        phototoxicity risk.