To Investigate the Safety, Tolerability and Pharmacodynamics of GSK2890457 in Healthy Volunteers and Subjects With Type 2 Diabetes
Condition: Obesity
MeSH terms: Obesity
Intervention: GSK2890457; Metformin; Placebo; Liraglutide
Intervention description: Provided as powder and capsule.; Tablet
Part A: Single doses on Day 1 and Day 42 orally
Part B: Subject continues usual metformin dose through Run-in, and resumes after Treatment Period completed
Part C: Subject continues usual metformin dose throughout study; Provided as powder and Capsule.; Provided as Injection. 6mg/mL, 3mL injector pen that permits doses of 0.6mg, 1.2mg, and 1.8mg
Subcutaneous injection 18 weeks dosing (Stabilization and Treatment Periods, Part B only
Intervention MeSH terms: Metformin; Liraglutide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: metformin; diabetes; obesity; liraglutide

Summary:

      This study is the first administration of GSK2890457 in humans. The study will be conducted
      in 3 parts: - Part A (conducted at a single investigative site) will determine the safety and
      tolerability of GSK2890457 alone in healthy subjects during six weeks of dosing, as well as
      evaluating the potential for a pharmacokinetic interaction with metformin. Part A consists of
      Screening, Treatment (6 weeks) and Follow-up periods. - Part B (conducted at multiple sites)
      will determine safety, tolerability, and pharmacodynamics (PD) in subjects with Type 2
      diabetes (T2D) when co-dosed for six weeks with liraglutide (Victoza). Part B consists of
      Screening, Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up
      periods. - Part C (conducted at multiple sites) will determine safety, tolerability, and PD
      in subjects with T2D when co-dosed for 6 weeks with metformin. Part C consists of Screening,
      Run-in (1 week), Stabilization (12 weeks), Treatment (6 weeks) and Follow-up periods.
    

Eligibility criteria:

        Inclusion Criteria:Part A (Healthy Subjects)

          -  Subject able to understand and voluntarily provide the consent to participate in the
             study

          -  18 - 70 years of age, inclusive, at the time of signing the informed consent and Body
             Mass Index (BMI) between 18.0 and 35.0 Kilogram (kg) per m^2, inclusive

          -  Understands and is willing, able and likely to be compliant with taking study drug and
             comply with all study procedures and restrictions

          -  Subject is willing to consume the foods that are part of the standardized breakfast,
             lunch, and dinner

          -  In good general health with no clinically significant and relevant abnormalities of
             medical history or physical examination which includes adequate renal function,
             alanine transaminase (ALT), alkaline phosphatase and bilirubin <=1.5x Upper Limit of
             Normal (ULN )

          -  QTcF < 450 millisecond (msec); or QTcF < 480msec for subjects with right Bundle Branch
             Block

          -  Females must be post-menopausal

          -  Females on hormone replacement therapy (HRT) must discontinue HRT to allow
             confirmation of post-menopausal status prior to study enrollment

          -  Females who are > 3 months postpartum and who have undergone a surgical sterilization
             procedure are eligible to participate in consultation with the GSK Medical Monitor

        Parts B and C (Type 2 Diabetic Subjects)

          -  All the criteria mentioned in Part A except Body Mass Index (BMI) should be between
             30.0 and 42.0 kg per m^2

          -  Diagnosis of T2D for at least 3 months, as defined by the American Diabetes
             Association

          -  All T2D subjects must meet label recommendations for metformin

          -  For Part B, subjects must be willing to discontinue metformin and replace it with
             daily liraglutide administered by subcutaneous injection and they must meet label
             recommendations

          -  No personal history or family history of medullary thyroid carcinoma or Multiple
             Endocrine Neoplasia syndrome type 2

        Exclusion Criteria:

          -  History of gastrointestinal disease, current or chronic history of liver disease,
             history of serious, severe or unstable physical or psychiatric illness , significant
             cardiovascular disease, surgery for weight loss or gastrointestinal surgery within 3
             months of screening, any documented or reported eating disorder, uncontrolled
             hypertension, as evidenced by systolic pressure>160 or diastolic pressure >90 mmHg

          -  Positive test for HIV, Hepatitis B, or Hepatitis C at Screening

          -  Subjects with significant ECG abnormalities

          -  For subjects in Part C (continuing metformin), history of untreated pernicious anemia
             or who have laboratory parameters suggestive of subclinical megaloblastic anemia

          -  Presence of or symptoms of an active infection

          -  Uncorrected Thyroid Dysfunction

          -  History of chronic or acute pancreatitis

          -  Currently dieting to lose weight including, but not limited to, participation in a
             program designed to alter body weight within the last 60 days and unwilling to
             maintain relatively consistent exercise patterns throughout the study

          -  Current or recent history (within one year of screening) of alcohol or other substance
             abuse

          -  Unable to refrain from the use of non-prescription drugs

          -  Current participation in another clinical study or participation in a clinical study
             involving an investigational drug within 30 days of the screening visit

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy

          -  An employee of the sponsor or the study site or members of their immediate family.