Study to Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 in Type 2 Diabetes Patients Taking Metformin
Condition: Diabetes Mellitus, Type 2
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: GSK2330672; Placebo; Metformin
Intervention description: GSK2330672 will be supplied as oral solution, and will be administered BID [45 mg (2 days repeat dose) and 90 mg (5 days repeat dose) in each period]; GSK2330672 matching placebo will be supplied as oral solution, and will be administered BID (7 days of dosing in each period); Metformin 850 mg will be administered BID from Run-in period till Day 7 of period 2
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 16.0
Sex: All
Minimum age: 30 Years
Maximum age: 64 Years
Healthy volunteers: No
Keywords: Metformin; Diabetes

Summary:

      Metformin may have complex interactions in the gut and is generally first line therapy for
      type 2 diabetes mellitus (T2DM). It is important to understand whether there are significant
      pharmacokinetic or pharmacodynamic interactions when GSK2330672 is co-administered with
      metformin in subjects with T2DM. The purpose of this study is to investigate the safety and
      tolerability of GSK2330672 administered for 7 days to subjects with T2DM taking metformin.
      This will be a two-period crossover study; subjects will receive either GSK2330672 or placebo
      for 7 days in each period separated by a washout period of 13 to 15 days. All subjects will
      receive metformin throughout the study
    

Eligibility criteria:

        Inclusion Criteria:

          -  Males and females aged between 30 and 64 years of age inclusive, at the time of
             signing the informed consent.

          -  Subjects with documented T2DM diagnosis (diagnosed not less than 3 months prior to
             screening); AND one of the following: taking stable metformin 850 milligrams (mg)
             twice daily (BID) (or the equivalent of 1700 mg/day) for at least 4 weeks prior to
             screening and a glycosolated haemoglobin A1c (HbA1c) of >=7.0% to <=11% at screening;
             OR taking stable metformin of >=1000 mg/day to <1700 mg/day for at least 4 weeks prior
             to screening and a HbA1c of >=7.5% to <=11% at Screening; OR taking stable metformin
             of >1700 to <=2000 mg/day for at least 4 weeks prior to screening and a HbA1c of
             >=7.0% to <=10% at screening; not taking other anti-diabetic medications.

          -  All T2DM subjects must meet label recommendations for metformin, including: Adequate
             renal function, as evidenced by the Modification of Diet in Renal Disease estimate of
             glomerular filtration rate >=60 milliliters (mL)/minute (min); No conditions which
             make hypoxia, dehydration, or sepsis likely; No clinical or laboratory evidence of
             hepatic disease (including history of cholecystitis or symptomatic gallstones) and
             cardiac disease (including a history of myocardial infarction or heart failure).
             Subjects with a history of cholelithiasis and uncomplicated cholecystectomy more than
             3 months before screening may be eligible if approved by the GlaxoSmithKline (GSK)
             Medical Monitor; No excessive alcohol intake.

          -  C-peptide of >0.8 nanogram (ng)/mL at screening visit.

          -  Urine albumin-to-creatinine ratio <30 mg/gram (g).

          -  Fasting plasma glucose <280 mg/decilitre (dL)

          -  Body mass index (BMI) of 24 to 40 kilograms (kg)/square meter (m^2), inclusive

          -  In good general health with (in the opinion of the investigator) no clinically
             significant and relevant abnormalities of medical history or physical examination that
             would introduce additional risk factors or interfere with study procedures or
             objectives, based on a medical evaluation including medical history, physical
             examination, vital signs and laboratory tests.

          -  Female subjects of non-childbearing potential. Non-childbearing potential is defined
             as: Pre-menopausal females with a documented tubal ligation or hysterectomy [for this
             definition, "documented" refers to the outcome of the investigator's/designee's review
             of the subject's medical history for study eligibility, as obtained via a verbal
             interview with the subject or from the subject's medical records]. Postmenopausal
             defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample
             with simultaneous follicle stimulating hormone (FSH) > 40 milli international units
             (MIU)/mL and estradiol < 40 picograms (pg)/mL (<147 picomole [pmol]/liter [L]) is
             confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status
             is in doubt will be required to use one of the acceptable contraception methods if
             they wish to continue their HRT during the study. Otherwise, they must discontinue HRT
             to allow confirmation of post-menopausal status prior to study enrollment. For most
             forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and
             the blood draw; this interval depends on the type and dosage of HRT. Following
             confirmation of their post-menopausal status, they can resume use of HRT during the
             study without use of a contraceptive method.

          -  Male subjects with female partners of child-bearing potential must agree to use one of
             the acceptable contraception methods. This criterion must be followed from the time of
             the first dose of study medication until follow up visit.

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form

        Exclusion Criteria:

          -  CRITERIA BASED UPON MEDICAL HISTORIES:

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome).

          -  History of chronic or acute pancreatitis. Approval from the GSK Medical Monitor must
             be obtained for subjects with a past history of pancreatitis more than 12 months from
             the start of the treatment period (subjects with a history of pancreatitis within 12
             months prior to the start of the treatment period are excluded).

          -  History of gastrointestinal (GI) disease (e.g., irritable bowel disease, chronic or
             current diarrhea, inflamed bowel, steatorrhoea/fat malabsorption, celiac disease,
             symptomatic lactose intolerance). Subjects with gastroparesis requiring treatment are
             excluded.

          -  History of significant cardiovascular disease including acute myocardial infarction,
             stroke, hospitalization for acute coronary syndrome, heart failure within the previous
             12 months.

          -  Uncontrolled hypertension, as evidenced by systolic pressure >160 or diastolic
             pressure >90. Subjects taking anti-hypertensive medications are permitted.

          -  Significant ECG abnormalities, defined as follows: Heart rate (resting) <50 and >100
             beats per minute (bpm); PR Interval <120 and >220 milliseconds (msec); QRS duration
             <70 and >120 msec

          -  History of untreated pernicious anemia or who have laboratory parameters suggestive of
             subclinical megaloblastic anemia (e.g., increased mean corpuscular volume with low red
             blood cells count and/or haemoglobin level).

          -  Current or relevant previous significant medical disorder that may require treatment
             or make the subject unlikely to fully complete the study, or any condition that, in
             the opinion of the investigator, presents undue risk from the study medication or
             procedures.

          -  Thyroid Disease: Uncorrected Thyroid Dysfunction: Fasting plasma thyroid stimulating
             hormone (TSH) outside of the normal range, as determined at the screening visit;
             Subjects on stable thyroid replacement therapy and with TSH in the normal range are
             eligible if approved by the GSK Medical Monitor; Unevaluated thyroid nodule or goiter
             at Screening.

          -  History of regular alcohol consumption within 6 months of the study defined as: An
             average weekly intake of >14 drinks for males or >7 drinks for females. One drink is
             equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine
             or 1.5 ounces (45 mL) of 80 proof distilled spirits.

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

          -  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 GSK
             Medical Monitor, contraindicates their participation

          -  CRITERIA BASED UPON DIAGNOSTIC ASSESSMENTS:

          -  Alanine transaminase, alkaline phosphatase and bilirubin > 1.5x upper limit of normal
             (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
             direct bilirubin <35%).

          -  Based on averaged QTcF values of triplicate ECGs obtained at least 1 minute apart
             within approximately 15 minutes: QTcF >=450 msec; or QTcF >=480 msec in subjects with
             Bundle Branch Block (subjects with left bundle branch block are excluded)

          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
             result within 3 months of screening

          -  A positive test for human immunodeficiency virus antibody

          -  A positive pre-study drug/alcohol urine screen

          -  A subject with a positive urine cotinine test result will be excluded from the study
             unless in the judgment of the Investigator the subject will be able to abstain from
             using tobacco for the duration of the in-house periods of the study.

          -  OTHER CRITERIA

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 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.

          -  A subject with a fasting plasma glucose at Day -1 that is more than 100 mg/dL lower
             than at screening must not be randomized, unless on a repeat test the value less than
             100 mg/dL of the screening value.