A Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients

Exclusion Criteria

• •The use of approved non-metformin anti-diabetic agents within 3 months of the screening visit
• •Hypoglycemia unawareness. T2DM subjects are excluded if, in the opinion of the investigator, they have significant hypoglycemia unawareness (for example, no symptoms of hypoglycemia when the blood glucose level is \<70 mg/dl)
• •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome). Subjects with a history of cholelithiasis, biliary colic, inflammatory gall bladder disease and/or cholestatic liver disease are excluded, unless this results in curative cholecystectomy 3 months or more before screening and with the approval of the GlaxoSmithKline (GSK) Medical Monitor
• •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). NOTE: Subjects with a lipase value above the upper limit of normal (ULN) at screening are excluded. A single repeat assessment is allowed within 3 days of the original test
• •History of Gastrointestinal (GI) disease (e.g., irritable bowel disease, chronic or current diarrhea, inflamed bowel, steatorrhoea/fat malabsorption, celiac disease, symptomatic lactose intolerance, small bowel resection). Subjects with gastroparesis requiring treatment are excluded. Subjects with history of prolapsed or bleeding haemorrhoids within 1 month of screening are excluded unless approved by the GSK Medical Monitor
• •History of autonomic neuropathy
• •History of epilepsy and/or use of anti-convulsants, including but not limited to phenobarbitone, phenytoin, carbamazepine, valproate
• •History of serious, severe, or unstable physical or psychiatric illness including depression, suicidal thoughts, schizophrenia, bipolar disorder, or generalized anxiety disorder. In addition to elicited symptoms and signs, this should include specific questions relating to known psychiatric diagnoses and medications used
• •History of significant cardiovascular disease not covered by the label recommendations for metformin, for example, ventricular tachyarrhythmias, peripheral arterial disease, and pulmonary embolism, within the previous 12 months
• •Uncontrolled hypertension, as evidenced by systolic pressure \>160 millimeters of mercury (mmHg) or diastolic pressure \>90 mmHg on a single assessment. If systolic pressure \>140 mmHg or diastolic pressure \>90 mmHg, a single repeat is allowed within 1 hour. Subjects whose blood pressure is well-controlled by taking anti-hypertensive medications (e.g., beta blockers, angiotensin converting enzyme(ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, and thiazide diuretics) are permitted
• •History of untreated pernicious anemia or who have laboratory parameters suggestive of subclinical megaloblastic anemia (e.g., increased mean corpuscular volume \[MCV\] with low red blood cells \[RBC\] count and/or haemoglobin \[Hb\] level).
• •C-peptide of \<0.8 nanogram (ng)/mL at screening
• •Urine albumin-to-creatinine ratio \>0.3 mg albumin/mg creatinine
• •Positive fecal occult blood test at screening or during the run-in period
• •Significant ECG abnormalities, defined as follows: Heart Rate (resting) was \<50 and \>100 beats per minute (bpm); PR Interval between \<120 and \>220 millisecond (msec); QRS duration between \<70 and \>120 msec
• •Based on averaged QTcF of triplicate ECGs obtained at least 1 minute apart within approximately 15 minutes: QT duration corrected for heart rate by Fridericia's formula (QTcF) \>= 450 msec; OR QTcF \>= 480 msec in subjects with right 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 HIV antibody
• •A positive urine drug screen or alcohol breath test at screening or during the run-in or treatment periods
• •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-clinic treatment period of the study
• •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
• •Subjects who have participated in a previous study with GSK2330672 are excluded
• •Because of the potential impact on bile acid synthesis and secretion in the liver, use of rifampicin and/or other pregnane X receptor (PXR) inducers, including but not limited to St. John's Wort, is cause for subject exclusion