Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects
Condition: Healthy Volunteers
Intervention: GSK3008356; Placebo
Intervention description: This intervention is available as 0.5, 1, 5, and 25 mg white oral tablet. The formulation will be used to administer dose of 5 mg, 10 mg, 30 mg, 45 mg, 75 mg, 90 mg, 125 mg, 180 mg, 200 mg, and 250 mg total daily dose during the study.; This intervention is available as white oral tablet. The formulation will be used as a matching placebo for GSK3008356 during the study.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 104.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Dose escalation study; Safety; Pharmacodynamics; Pharmacokinetics; GSK3008356; Tolerability

Summary:

      This study is a phase I, randomized, placebo-controlled, double-blind (sponsor unblind),
      three part study. The primary objective of the study is to characterize the safety, and
      tolerability of GSK3008356 single dose, 14 daily repeat doses in healthy subjects and 28
      daily repeat doses in obese subjects. The study has three parts. Part 1, will be a single and
      multiple-dose, dose-rising study in healthy subjects. Part 2, will be a 14-day, repeat-dose,
      dose-rising study in healthy subjects, and part 3 will be a 28-day, repeat-dose study in
      obese subjects. For Parts 1 and 2, data from prior doses cohorts will be available prior to
      escalation decisions. Data from Parts 1 and 2 will be available prior to initiation of the
      three parallel cohorts in Part 3. A dose escalation meeting will be held to review these data
      and document the decision to proceed as planned or make any alterations in dosing, if
      indicated. Part 1, Part 2 and Part 3 study will have approximately 88, 24 and 30 subjects,
      respectively.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

          -  For Part 1 and Part 2: Healthy as determined by the investigator or medically
             qualified designee based on a medical evaluation including medical history, physical
             examination, laboratory tests and cardiac monitoring.

          -  For Part 3: Obese subjects may have chronic disease not specifically excluded and not
             requiring chronic medication for treatment and are otherwise healthy as determined by
             the investigator or medically qualified designee based on a medical evaluation
             including medical history, physical examination, laboratory tests and cardiac
             monitoring. A subject with a clinical abnormality or laboratory parameter(s) which
             is/are not specifically listed in the inclusion or exclusion criteria, outside the
             reference range for the population being studied may be included only if the
             investigator in consultation with the Medical Monitor agree and document that the
             finding is unlikely to introduce additional risk factors and will not interfere with
             the study procedures.

          -  Body weight >=50 kilograms (kg)

          -  For Part 1 and Part 2 body mass index (BMI) 19-25 kilogram per meter square
             (inclusive)

          -  For Part 3 BMI >=30 kilogram per meter square

          -  Males or Females of non-childbearing potential as follows: Male subjects with female
             partners of child bearing potential must comply with the following contraception
             requirements from the time of first dose of study medication until at least five
             half-lives of study medication after the last dose of study medication.

               1. Vasectomy with documentation of azoospermia.

               2. Male condom plus partner use of one of the following contraceptive options:
                  Contraceptive subdermal implant; Intrauterine device or intrauterine system; Oral
                  Contraceptive, either combined or progestogen alone; Injectable progestogen;
                  Contraceptive vaginal ring; Percutaneous contraceptive patches

          -  Males or Females of non-childbearing potential as follows: A female subject is
             eligible to participate if she is not pregnant (as confirmed by a negative serum human
             chorionic gonadotrophin [hCG] test), not lactating, and the following condition
             applies:

        Non-reproductive potential defined as: Pre-menopausal females with one of the following:
        Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with
        follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral
        Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable
        cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40
        milli-international units per milliliter (MlU/ml) and estradiol < 40 picograms (pg) per ml
        (<147 picomoles per liter (pmol/L) is confirmatory. Females on hormone replacement therapy
        (HRT) and whose menopausal status is in doubt will not be allowed.

        The investigator is responsible for ensuring that subjects understand how to properly use
        these methods of contraception.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

        Exclusion Criteria:

          -  Alanine aminotransferase (ALT) and bilirubin >1.5 times upper limit of normal
             (isolated bilirubin >1.5 times upper limit of normal is acceptable if bilirubin is
             fractionated and direct bilirubin <35%).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  QTcF >450 millisecond (msec)

          -  Current or chronic history of gastrointestinal illness or conditions interfering with
             normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass
             surgery, cholecystectomy, partial or total gastrectomy, small bowel resection,
             vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome
             (IBS), or celiac sprue.

          -  Use of prescription or non-prescription drugs, including 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 the first
             dose of study drug, unless in the opinion of the Investigator and GlaxoSmithKline
             (GSK) Medical Monitor the medication will not interfere with the study procedures or
             compromise subject safety. By exception, subject may take acetaminophen (<=2 grams per
             day) up to 48 hours prior to the first dose of study drug.

          -  Subjects should refrain from consumption of red wine, Seville oranges, grapefruit or
             grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit
             juices from 7 days prior to the first dose of study medication until after the final
             dose.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >14 standard drinks. One standard drink is equivalent to 10
             grams of alcohol: 285 milliliter (mL) of beer, 100 mL of wine or 30 mL of 40% alcohol
             by volume distilled spirits.

          -  For Part 1 and Part 2, 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 sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or Medical
             Monitor, contraindicates their participation.

          -  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. For
             potent immunosuppressive agents, subjects with presence of hepatitis B core antibody
             (HBcAb) should also be excluded.

          -  A positive pre-study drug/alcohol screen.

          -  A positive test for human immunodeficiency virus (HIV) antibody.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 750 mL within 90 day period.

          -  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: 30 days, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.