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

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT02202161

Collaborator

(none)

Enrollment

Locations

Arms

5.1

Actual Duration (Months)

17.5

Patients Per Site

3.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is being conducted to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK2330672 compared to sitagliptin when administered with metformin for 14 days to subjects with type 2 diabetes mellitus (T2DM). Approximately 72 male and female subjects aged 30-64 years with T2DM and currently taking metformin will be recruited for this study. Eligible subjects will begin a run-in period of 13-15 days to stabilize on metformin 850 milligram (mg) twice a day (BID). Subjects will then be randomized to GSK2330672 10 mg, 20 mg, 30 mg, 90 mg, matching placebo or open-label sitagliptin 50 mg for 14 days BID. Subjects will return for a follow-up visit 7-10 days after discharge.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: GSK2330672 Drug: Placebo Drug: Sitagliptin Drug: Metformin	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized, Placebo Controlled, Repeat Dose, Double Blind (Sponsor Unblind) Study Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2330672 Administered With Metformin to Type 2 Diabetes Patients

Actual Study Start Date :

Aug 27, 2014

Actual Primary Completion Date :

Jan 30, 2015

Actual Study Completion Date :

Jan 30, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GSK2330672 10 mg Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 10 mg BID for 14 days.	Drug: GSK2330672 GSK2330672 will be available in 10 mg, 20 mg, 30 mg, and 90 mg oral solution to be administered BID for 14 days. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
Experimental: GSK2330672 20 mg Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 20 mg BID for 14 days.	Drug: GSK2330672 GSK2330672 will be available in 10 mg, 20 mg, 30 mg, and 90 mg oral solution to be administered BID for 14 days. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
Experimental: GSK2330672 30 mg Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 30 mg BID for 14 days.	Drug: GSK2330672 GSK2330672 will be available in 10 mg, 20 mg, 30 mg, and 90 mg oral solution to be administered BID for 14 days. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
Experimental: GSK2330672 90 mg Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by GSK2330672 90 mg BID for 14 days.	Drug: GSK2330672 GSK2330672 will be available in 10 mg, 20 mg, 30 mg, and 90 mg oral solution to be administered BID for 14 days. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
Placebo Comparator: GSK2330672-matched placebo Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by matching placebo (of GSK2330672) BID for 14 days.	Drug: Placebo Matching placebo will be available as oral solution to be administered for 14 days, BID. Subjects are to drink contents of dosing bottle (45 ml) followed by 2 x 50 ml rinses of bottle and then an additional 95 ml water for a total volume of 240 ml consumed Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14
Active Comparator: Sitagliptin 50 mg Subjects will receive metformin 850 mg BID for 13-15 days during the run in period followed by Sitagliptin 50 mg BID for 14 days. In this study, sitagliptin 50 mg BID will be provided as open-label (unblinded) study treatment.	Drug: Sitagliptin Sitagliptin will be available as film-coated tablets Tablet of 50 mg to be administered orally, BID, for 14 days Drug: Metformin Metformin will be available as 850 mg white to off-white, film-coated tablets; to be administered BID orally during run-in through Day 14

Outcome Measures

Primary Outcome Measures

Change From Baseline in Derived Plasma Glucose Parameter Over a 24-hour Period-fasting and Weighted Mean Glucose Area Under Curve (AUC[0-24 Hour]) [Baseline (Day -1) and Day 14 (Fasting Pre-dose [within 15 minutes of dose], 30 minutes, 1, 1.5, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, 14 [bed time] and 24 hours) and Day 7 (30 minutes, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, and 24 hours)]
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value. It was assessed on Baseline, Day 7 and 14. Data for fasting and weighted mean (WM) AUC(0-24 hour) glucose is provided. Statistics for least square mean is provided and participants withdrawing early were excluded. Results were based on an analysis of covariance (ANCOVA) model: change from Baseline = Baseline + treatment.
Number of Participants With Incidence and Nature of Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 14 days (treatment period)]
An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition and alanine aminotransferase (ALT) >= 3× upper limit of normal (ULN) and total bilirubin >=2 × ULN (>35% direct) or ALT >=3 × ULN and international normalized ratio >1.5.
Number of Participants With Abnormal Hematology With Potential Clinical Concern (PCI) [Up to Day 15]
Hematology parameters included platelet, red blood cell (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided.
Number of Participants With Abnormal Clinical Chemistry With PCI [Up to Day 15]
Clinical chemistry parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, fasting glucose, total carbon dioxide, gamma glutamyltransferase (GGT), albumin, sodium, calcium, alkaline phosphatase (ALP), total protein, total carbon dioxide and triglycerides. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided. The normal range (NR) and PCI definition for abnormal parameters are: ALT (NR: 0-44, 0-32, 2-33; PCI: >=2×upper limit of normal [ULN]); AST (NR: 0-40; PCI: >=2× ULN) and total bilirubin (NR: 0.00-20.52; PCI: >=1.5× ULN).
Number of Participants With Abnormal Urinalysis Data [Baseline (pre-dose Day -1), Day 7 and 15]
Urinalysis included urine occult blood: trace to 3+, glucose: negative to 3+, protein: negative to 2+ and ketones: trace to negative by dipstick and microscopic examination included cast, cellular cast, granular cast, hyaline cast (none seen to 1) and RBC: 0-2, 3-10, 11-30, >30, WBC: none seen, 0-5, 1, 2, 4, <5, 6-10, 11-30, 19, >30). The plus sign increases with a higher level of occult blood, glucose, ketones, proteins, RBC, WBC in the urine: 1+: slightly positive, 2+: positive, 3+: high positive. Participants were categorized as none seen or 1 based on the absence or presence, respectively, of cast, cellular cast, granular cast and hyaline cast. Higher value indicates higher abnormality.
Summary of Urinalysis Data-mean Specific Gravity [Baseline (pre-dose Day -1), Day 7 and 15]
Data for mean specific gravity is provided. Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020.
Summary of Urinalysis Data-mean pH [Baseline (pre-dose Day -1), Day 7 and 15]
Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Number of Participants With Abnormal Electrocardiogram (ECG) Findings Any Time Post-Baseline [Up to Day 15]
Single 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Participants with normal, abnormal not clinically significant and abnormal clinically significant ECG is presented.
Change From Baseline in Vital Signs Assessments-temperature [Baseline (pre-dose Day -1) and, Day 7, 15]
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Change From Baseline in Vital Signs Assessments-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [Baseline (pre-dose Day -1) and Day 7, 15]
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Change From Baseline in Vital Signs Assessments-heart Rate [Baseline (pre-dose Day -1) and Day 7, 15]
The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Number of Bowel Movements (Stool Frequency) as Rated Using the Bristol Stool Form Scale (BSFS) Across Days 1 to 14 [Up to Day 15 (administered after every in-house bowel movement)]
The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Number of Events With the Rating on Quality of Stools as Rated Using the BSFS Across Days 1 to 14 [Up to Day 15 (administered after every in-house bowel movement)]
The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Number of Participants With Gastrointestinal Tolerability Assessments as Rated Using the Gastrointestinal Symptom Rating Scale (GSRS; With Worsening Symptoms >=2 Levels) [Day 7 and 14]
GSRS is a rating scale consisting of 15 items. Each item was scored from 1: no discomfort at all, 2: minor discomfort, 3: mild discomfort, 4: moderate discomfort, 5: moderately severe discomfort, 6: severe discomfort, 7: very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 1 to 7; a score of 1 indicates that no symptoms are present, and a score of 7 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. There were 5 defined syndrome scores and 1 overall score that was derived by computing the mean of the scores for specific subsets of questions as indicated below: abdominal pain (1, 4, 5); reflux syndrome (2, 3); diarrhea syndrome (11, 12, 14); indigestion syndrome (6, 7, 8, 9); constipation syndrome (10, 13, 15) and overall GSRS (1-15). The data is presented for participants with worsening of symptoms in >=2 levels.
Number of Participants With Fecal Occult Blood Monitoring for Symptomatic or Visible Gastrointestinal Bleeding or Asymptomatic Occult Bleeding [Up to Day 15]
Testing cards were provided to participants for assessments. Participants with abnormal not clinically significant and abnormal clinically significant is presented. The Day -1 sample was obtained any time starting Day -2 and prior to GSK2330672 dosing on Day 1. The Day 14 sample was collected any time after dosing on Day 14 and prior to discharge on Day 15.

Secondary Outcome Measures

PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-maximum Observed Concentration (Cmax) [Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14]
The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Statistics for geometric least square mean provided.
PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-time of Occurrence of Cmax (Tmax) [Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14]
The time at which Cmax observed was determined directly from the raw concentration-time data.
PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-area Under the Concentration-time Curve Over the Dosing Interval of 10 Hours (AUC[0-10]) [Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14]
PK population. Only those participants available at the specified time points were analyzed.
Ratio to Baseline in Fasting Low-density Cholesterol (LDL) Cholesterol, High-density Cholesterol (HDL) Cholesterol, Total Cholesterol, Non-HDL Cholesterol and Triglycerides [Baseline (pre-dose Day -1) and Day 7, 14]
Data for fasting low-density cholesterol (LDL) cholesterol, high-density cholesterol (HDL) cholesterol, total cholesterol, non-HDL cholesterol and triglycerides is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
Ratio to Baseline in Fasting Apolipoprotein B [Baseline (pre-dose Day -1) and Day 7, 14]
Data for fasting apolipoprotein B is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Cmax Following the First and Second Sitagliptin Doses [Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14]
The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Cmax1 and Cmax2).
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Tmax Following the First and Second Sitagliptin Doses [Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14]
The time at which Cmax was observed by determining directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Tmax1 and Tmax2). If data permits, Tmax2 was defined as the time of Cmax following the second dose of sitagliptin.
Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-AUC(0-10) [Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner) on Day 14]
The AUC(0-10) following the first dose and prior to the second dose of sitagliptin was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female between 30 and 64 years of age inclusive, at the time of signing the informed consent
Subjects with a diagnosis of T2DM for at least 3 months prior to screening, taking metformin for at least 4 weeks prior to screening, taking a metformin daily dose of>= 1000 mg and having an Glycosolated haemoglobin A1c (HbA1c) value of 7-11% inclusive at screening. The investigator should make an effort to obtain documentation of medical history or prescription of metformin to substantiate the diagnosis of T2DM
Fasting plasma glucose <280 milligram per deciliter (mg/dl) at screening. A subject with a fasting plasma glucose at Day 1 that is more than 100 mg/dl lower than the screening value must not be randomized
All T2DM subjects must meet the label recommendations for metformin and sitagliptin, including: Adequate renal function, as evidenced by an estimated glomerular filtration rate >= 80 milliliter per minute (mL/min) using the modification of diet in renal disease (MDRD) equation or chronic kidney disease epidemiology collaboration (CKD-EPI) formula in the study procedures manual (SPM); No conditions which make hypoxia, dehydration, or sepsis likely; No cardiac disease (including no history of myocardial infarction, stroke, hospitalization for acute coronary syndrome, or heart failure)
Body mass index (BMI) within the range 24 - 40 kilogram per meter square (kg/m^2) (inclusive)
Other than T2DM, subjects should be 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
A female subject is eligible to participate if she is of non-childbearing potential defined as: Pre-menopausal females with a documented tubal ligation, bilateral oophorectomy, 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]; OR Postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)

40 million international units (MlU)/mL and estradiol < 40 picogram (pg)/mL (<147 picomol per liter) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods as described by the Investigator/designee, 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 2-4 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 contraception methods as described by the Investigator/designee. This criterion must be followed from the time of the first dose of study medication until the follow-up visit
Subjects must be willing to discontinue their usual dose of metformin and take the study dose of 850 mg immediate release formulation metformin BID for the 13-15 day run-in period and the 2-week treatment period
Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

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).
Thyroid disease: Uncorrected Thyroid Dysfunction as 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 gram (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 (including other Dipeptidyl Peptidase-IV [DPP-IV] inhibitors) that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
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
Alanine aminotransferase (ALT)>2xULN and bilirubin >1.5xULN (isolated bilirubin

1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

Fasting triglycerides >= 400 mg/dl for subjects without a history of pancreatitis or

250 mg/dl for subjects with a history of 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). Subjects taking statins, ezetimibe, or Vytorin are permitted in the study. Subjects taking other lipid therapies, including but not limited to niacin, bile acid sequestrants and/or fibrates are not eligible

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Chula Vista	California	United States	91910
2	GSK Investigational Site	Miami	Florida	United States	33169
3	GSK Investigational Site	Baltimore	Maryland	United States	21225
4	GSK Investigational Site	San Antonio	Texas	United States	78209

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02202161

Other Study ID Numbers:

201351

First Posted:

Jul 28, 2014

Last Update Posted:

Nov 6, 2017

Last Verified:

Aug 1, 2017

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

pharmacokinetic

intestinal bile acid transporter inhibitor

Additional relevant MeSH terms:

Diabetes Mellitus

Diabetes Mellitus, Type 2

Metformin

Sitagliptin Phosphate

Study Results

Participant Flow

Recruitment Details	The study was conducted from 27 August 2014 to 30 January 2015. After interim analysis of safety, tolerability, pharmacodynamic and/or pharmacokinetic (PK) data, GSK2330672 10 and 20 milligram (mg) doses were dropped and GSK2330672 60 mg was added.
Pre-assignment Detail	A total of 187 participants were screened, of these, 112 were screen failures and 75 entered the run-in period. Five participants were withdrawn prior to taking a metformin dose in the 14 days of run-in period. A total of 64 participants were randomized to receive investigational product, as 6 participants were withdrawn prior to randomization.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID	Run-in Only
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally twice daily (BID) for 14 days. Participants drank the contents of dosing bottle (45 milliliters [mL]) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.	Participants were received open label metformin 850 mg tablet BID during run-in period, but were withdrawn prior to randomization. Participants swallowed the whole tablet with 240 mL of water and were instructed to avoid chewing or crushing.
Period Title: Overall Study
STARTED	13	5	5	9	9	10	13	6
COMPLETED	12	4	5	9	8	9	13	0
NOT COMPLETED	1	1	0	0	1	1	0	6

Baseline Characteristics

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID	Run-in Only	Total
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.	Participants were received open label metformin 850 mg tablet BID during run-in period, but were withdrawn prior to randomization. Participants swallowed the whole tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Total of all reporting groups
Overall Participants	13	5	5	9	9	10	13	6	70
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.1 (6.97)	54.0 (4.30)	56.2 (8.50)	57.1 (5.86)	55.0 (4.27)	54.8 (7.47)	53.7 (6.79)	55.5 (3.51)	54.5 (6.20)
Sex: Female, Male (Count of Participants)
Female	4 30.8%	3 60%	4 80%	2 22.2%	6 66.7%	4 40%	5 38.5%	3 50%	31 44.3%
Male	9 69.2%	2 40%	1 20%	7 77.8%	3 33.3%	6 60%	8 61.5%	3 50%	39 55.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%	0 0%	1 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 20%	0 0%	2 22.2%	0 0%	0 0%	0 0%	3 4.3%
Black or African American	3 23.1%	1 20%	0 0%	1 11.1%	3 33.3%	0 0%	3 23.1%	1 16.7%	12 17.1%
White	10 76.9%	4 80%	4 80%	8 88.9%	4 44.4%	9 90%	10 76.9%	5 83.3%	54 77.1%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Derived Plasma Glucose Parameter Over a 24-hour Period-fasting and Weighted Mean Glucose Area Under Curve (AUC[0-24 Hour])
Description	The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value. It was assessed on Baseline, Day 7 and 14. Data for fasting and weighted mean (WM) AUC(0-24 hour) glucose is provided. Statistics for least square mean is provided and participants withdrawing early were excluded. Results were based on an analysis of covariance (ANCOVA) model: change from Baseline = Baseline + treatment.
Time Frame	Baseline (Day -1) and Day 14 (Fasting Pre-dose [within 15 minutes of dose], 30 minutes, 1, 1.5, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, 14 [bed time] and 24 hours) and Day 7 (30 minutes, 2, 4 [pre-lunch], 5.5, 10 [pre-dinner], 11.5, and 24 hours)

Outcome Measure Data

Analysis Population Description
Safety population was used which was defined as all participants enrolled into the study who received at least one dose of study drug (including GSK2330672, GSK2330672-matched placebo, sitagliptin and metformin). Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Fasting, Day 7	-6.58 (16.357)	-8.25 (6.500)	-1.40 (23.050)	-38.56 (24.744)	-34.38 (19.398)	-24.78 (13.414)	-24.54 (33.955)
Fasting, Day 14	-10.00 (19.207)	-22.75 (11.354)	-16.20 (28.709)	-48.67 (32.650)	-36.13 (23.117)	-40.22 (19.156)	-38.38 (16.439)
WM AUC(0-24 hour), Day 7	3.91 (20.668)	-12.14 (11.828)	-7.01 (17.262)	-25.33 (25.819)	-21.47 (18.419)	-14.84 (18.569)	-26.63 (23.610)
WM AUC(0-24 hour), Day 14	-9.94 (18.458)	-22.44 (15.928)	-17.80 (16.990)	-37.48 (32.909)	-32.22 (22.948)	-45.54 (21.010)	-35.85 (20.233)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95% -25.61 to 23.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	13.22
	Confidence Interval	(2-Sided) 95% -9.84 to 36.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.77
	Confidence Interval	(2-Sided) 95% -41.43 to -2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.10
	Confidence Interval	(2-Sided) 95% -42.63 to -3.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11.79
	Confidence Interval	(2-Sided) 95% -30.85 to 7.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.04
	Confidence Interval	(2-Sided) 95% -27.66 to 7.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 7

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-15.14
	Confidence Interval	(2-Sided) 95% -37.72 to 7.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.10
	Confidence Interval	(2-Sided) 95% -23.66 to 19.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-20.66
	Confidence Interval	(2-Sided) 95% -38.75 to -2.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.70
	Confidence Interval	(2-Sided) 95% -39.70 to -3.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.62
	Confidence Interval	(2-Sided) 95% -28.62 to 7.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-26.03
	Confidence Interval	(2-Sided) 95% -41.94 to -10.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 7

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-12.10
	Confidence Interval	(2-Sided) 95% -33.56 to 9.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.33
	Confidence Interval	(2-Sided) 95% -15.91 to 24.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-25.29
	Confidence Interval	(2-Sided) 95% -42.56 to -8.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-19.97
	Confidence Interval	(2-Sided) 95% -37.12 to -2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.82
	Confidence Interval	(2-Sided) 95% -38.56 to -5.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-18.01
	Confidence Interval	(2-Sided) 95% -33.48 to -2.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for fasting, Day 14

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-11.20
	Confidence Interval	(2-Sided) 95% -33.21 to 10.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	4.80
	Confidence Interval	(2-Sided) 95% -16.22 to 25.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-15.23
	Confidence Interval	(2-Sided) 95% -32.86 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-17.01
	Confidence Interval	(2-Sided) 95% -34.56 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-23.94
	Confidence Interval	(2-Sided) 95% -41.49 to -6.39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	An analysis of covariance (ANCOVA) model with a fixed effect term for treatment was fitted with the post-Baseline pharmacodynamic parameter value minus Baseline (Day -1 parameter value) as the dependent variable and Baseline as a covariate.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-19.45
	Confidence Interval	(2-Sided) 95% -34.96 to -3.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for WM AUC(0-24 hour), Day 14

2. Primary Outcome

Title	Number of Participants With Incidence and Nature of Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was defined as any untoward medical occurrence (MO) in a participant temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. The SAE was any untoward MO that, at any dose, results in death, life threatening, persistent or significant disability/incapacity, results in or prolongs inpatient hospitalization, congenital abnormality or birth defect, that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition and alanine aminotransferase (ALT) >= 3× upper limit of normal (ULN) and total bilirubin >=2 × ULN (>35% direct) or ALT >=3 × ULN and international normalized ratio >1.5.
Time Frame	Up to 14 days (treatment period)

Outcome Measure Data

Analysis Population Description
Safety population.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Any AE	9 69.2%	4 80%	5 100%	5 55.6%	8 88.9%	8 80%	8 61.5%
Any SAE	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%	0 0%

3. Primary Outcome

Title	Number of Participants With Abnormal Hematology With Potential Clinical Concern (PCI)
Description	Hematology parameters included platelet, red blood cell (RBC) count, mean corpuscular volume (MCV), neutrophils, white blood cell (WBC) count (absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided.
Time Frame	Up to Day 15

Outcome Measure Data

Analysis Population Description
Safety population

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%

4. Primary Outcome

Title	Number of Participants With Abnormal Clinical Chemistry With PCI
Description	Clinical chemistry parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total bilirubin, direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, fasting glucose, total carbon dioxide, gamma glutamyltransferase (GGT), albumin, sodium, calcium, alkaline phosphatase (ALP), total protein, total carbon dioxide and triglycerides. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Data for parameters with above and below the PCI is provided. The normal range (NR) and PCI definition for abnormal parameters are: ALT (NR: 0-44, 0-32, 2-33; PCI: >=2×upper limit of normal [ULN]); AST (NR: 0-40; PCI: >=2× ULN) and total bilirubin (NR: 0.00-20.52; PCI: >=1.5× ULN).
Time Frame	Up to Day 15

Outcome Measure Data

Analysis Population Description
Safety population.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
ALT, high	1 7.7%	0 0%	2 40%	2 22.2%	2 22.2%	1 10%	1 7.7%
AST, high	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Total Bilirubin, hgh	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%

5. Primary Outcome

Title	Number of Participants With Abnormal Urinalysis Data
Description	Urinalysis included urine occult blood: trace to 3+, glucose: negative to 3+, protein: negative to 2+ and ketones: trace to negative by dipstick and microscopic examination included cast, cellular cast, granular cast, hyaline cast (none seen to 1) and RBC: 0-2, 3-10, 11-30, >30, WBC: none seen, 0-5, 1, 2, 4, <5, 6-10, 11-30, 19, >30). The plus sign increases with a higher level of occult blood, glucose, ketones, proteins, RBC, WBC in the urine: 1+: slightly positive, 2+: positive, 3+: high positive. Participants were categorized as none seen or 1 based on the absence or presence, respectively, of cast, cellular cast, granular cast and hyaline cast. Higher value indicates higher abnormality.
Time Frame	Baseline (pre-dose Day -1), Day 7 and 15

Outcome Measure Data

Analysis Population Description
Safety population.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Urine Occult Blood, Day -1, Trace	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Occult Blood, Day -1, small	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Occult Blood, Day-1, 3+	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%	0 0%
Urine Occult Blood, Day 7, Trace	0 0%	1 20%	1 20%	0 0%	0 0%	0 0%	1 7.7%
Urine Occult Blood, Day 7, Trace intact	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Occult Blood, Day 7, small	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Occult Blood, Day 7, 1+	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Occult Blood, Day 15, Trace	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Occult Blood, Day 15, small	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Occult Blood, Day 15, 2+	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Urine Microscopy-Casts, Day 7, none seen	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-Cellular Casts, Day -1, none seen	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 7.7%
Urine Microscopy-Cellular Casts, Day 7, none seen	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	1 7.7%
Urine Microscopy-Cellular Casts, Day 15, none seen	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	1 7.7%
Urine Microscopy-Granular Casts, Day -1, none seen	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 7.7%
Urine Microscopy-Granular Casts, Day 7, none seen	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	1 7.7%
Urine Microscopy-Granular Casts, Day 15, none seen	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	1 7.7%
Urine Glucose, Day -1, Trace	1 7.7%	0 0%	1 20%	1 11.1%	1 11.1%	2 20%	0 0%
Urine Glucose, Day -1, 1+	0 0%	0 0%	0 0%	3 33.3%	0 0%	0 0%	0 0%
Urine Glucose, Day -1, 2+	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Glucose, Day -1, 3+	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	2 15.4%
Urine Glucose, Day 7, Trace	0 0%	0 0%	0 0%	2 22.2%	1 11.1%	1 10%	1 7.7%
Urine Glucose, Day 7, 1+	1 7.7%	0 0%	1 20%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-Hyaline Casts, Day -1, none seen	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 7.7%
Urine Microscopy-Hyaline Casts, Day 7, None seen	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	1 7.7%
Urine Microscopy-Hyaline Casts, Day 7, 1	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Microscopy-Hyaline Casts, Day 15, none seen	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	1 7.7%
Urine Ketones, Day 7, Trace	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Urine Protein, Day -1, 1+	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%	0 0%
Urine Protein, Day 7, 2+	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%	0 0%
Urine Protein, Day 15, Trace	1 7.7%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%
Urine Protein, Day 15, 1+	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%	0 0%
Urine Microscopy-RBC, Day -1, none seen	2 15.4%	0 0%	0 0%	1 11.1%	0 0%	0 0%	1 7.7%
Urine Microscopy-RBC, Day -1, 0-2	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-RBC, Day -1, 3-10	0 0%	1 20%	1 20%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-RBC, Day -1, 11-30	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%	0 0%
Urine Microscopy-RBC, Day 7, none seen	1 7.7%	1 20%	0 0%	0 0%	0 0%	0 0%	2 15.4%
Urine Microscopy-RBC, Day 7, 0-2	0 0%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Urine Microscopy-RBC, Day 15, none seen	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%	1 7.7%
Urine Microscopy-RBC, Day 7, 3-10	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day -1, none seen	2 15.4%	2 40%	0 0%	1 11.1%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day -1, 0-5	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Urine Microscopy-WBC, Day -1, 1	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Microscopy-WBC, Day -1, 4	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day -1, 6-10	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Urine Microscopy-WBC, Day -1, 11-30	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day -1, >30	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 7, 0-5	1 7.7%	1 20%	1 20%	0 0%	0 0%	0 0%	0 0%
Urine Microscopy-WBC, Day 7, 1	0 0%	0 0%	0 0%	0 0%	2 22.2%	0 0%	0 0%
Urine Microscopy-WBC, Day 7, <5	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 7, 11-30	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	1 7.7%
Urine Microscopy-WBC, Day 7, 19	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 7, >30	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 15, 0-5	1 7.7%	0 0%	1 20%	1 11.1%	0 0%	0 0%	0 0%
Urine Microscopy-WBC, Day 15, 1	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 15, 2	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Microscopy-WBC, Day 15, 4	0 0%	0 0%	0 0%	0 0%	1 11.1%	0 0%	0 0%
Urine Microscopy-WBC, Day 15, 11-30	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Urine Microscopy-WBC, Day 15, >30	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%

6. Primary Outcome

Title	Summary of Urinalysis Data-mean Specific Gravity
Description	Data for mean specific gravity is provided. Specific gravity is a measure of the amount of material dissolved in the urine. Specific gravity is the ratio of the density (mass of a unit volume) of a substance to the density (mass of the same unit volume) of a reference substance. Normal urine has a specific gravity between 1.010 and 1.020.
Time Frame	Baseline (pre-dose Day -1), Day 7 and 15

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Day -1	1.0193 (0.00694)	1.0182 (0.00581)	1.0128 (0.00421)	1.0190 (0.00618)	1.0172 (0.00610)	1.0189 (0.00780)	1.0148 (0.00706)
Day 7	1.0196 (0.00753)	1.0208 (0.00904)	1.0184 (0.00896)	1.0191 (0.00739)	1.0194 (0.00726)	1.0208 (0.00859)	1.0160 (0.00790)
Day 15	1.0188 (0.00403)	1.0193 (0.00435)	1.0158 (0.00259)	1.0132 (0.00471)	1.0121 (0.00348)	1.0160 (0.00787)	1.0140 (0.00815)

7. Primary Outcome

Title	Summary of Urinalysis Data-mean pH
Description	Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Time Frame	Baseline (pre-dose Day -1), Day 7 and 15

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Day -1	5.73 (0.388)	6.00 (0.000)	6.10 (0.224)	6.11 (0.220)	5.83 (0.354)	5.95 (0.438)	5.85 (0.516)
Day 7	5.83 (0.389)	5.90 (0.224)	6.00 (0.000)	5.89 (0.220)	5.61 (0.486)	5.95 (0.284)	5.69 (0.435)
Day 15	5.88 (0.377)	5.88 (0.250)	6.00 (0.000)	6.00 (0.000)	5.72 (0.565)	6.06 (0.167)	5.88 (0.416)

8. Primary Outcome

Title	Number of Participants With Abnormal Electrocardiogram (ECG) Findings Any Time Post-Baseline
Description	Single 12-lead ECGs was obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. It was assessed on Baseline (pre-dose Day -1), Day 7 and 15. Participants with normal, abnormal not clinically significant and abnormal clinically significant ECG is presented.
Time Frame	Up to Day 15

Outcome Measure Data

Analysis Population Description
Safety population

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Normal	9 69.2%	4 80%	4 80%	8 88.9%	6 66.7%	6 60%	9 69.2%
Abnormal not clinically significant	4 30.8%	0 0%	1 20%	1 11.1%	3 33.3%	4 40%	4 30.8%
Abnormal clinically significant	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%	0 0%

9. Primary Outcome

Title	Change From Baseline in Vital Signs Assessments-temperature
Description	The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time Frame	Baseline (pre-dose Day -1) and, Day 7, 15

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Day 7	-0.133 (0.2570)	-0.280 (0.4764)	0.040 (0.4393)	0.033 (0.3937)	0.033 (0.2062)	0.010 (0.4458)	0.015 (0.4451)
Day 15	-0.208 (0.3370)	0.025 (0.1708)	-0.040 (0.2966)	-0.111 (0.5622)	0.056 (0.2744)	-0.178 (0.5995)	0.062 (0.3404)

10. Primary Outcome

Title	Change From Baseline in Vital Signs Assessments-systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Description	The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time Frame	Baseline (pre-dose Day -1) and Day 7, 15

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
DBP, Day 7	-0.083 (6.8152)	-1.600 (8.5323)	-6.600 (1.9494)	-1.556 (10.7948)	-4.111 (4.9861)	-2.700 (6.7007)	-2.462 (7.6770)
DBP, Day 15	0.750 (6.1070)	-2.750 (4.5735)	1.800 (5.8481)	-1.333 (9.1104)	-1.667 (3.9370)	-2.667 (6.3048)	-0.769 (5.0852)
SBP, Day 7	2.250 (8.4544)	-4.000 (10.2225)	-15.600 (6.1482)	2.222 (17.6973)	1.222 (9.1211)	-4.300 (10.9245)	-5.462 (10.3571)
SBP, Day 15	2.167 (8.5049)	-4.500 (10.4722)	0.600 (11.8870)	-5.111 (11.9105)	-1.000 (9.3541)	-2.111 (9.5321)	-4.385 (9.2334)

11. Primary Outcome

Title	Change From Baseline in Vital Signs Assessments-heart Rate
Description	The change from Baseline was calculated by subtracting the Baseline values from the individual post-Baseline values. Baseline was defined as pre-dose Day -1 value.
Time Frame	Baseline (pre-dose Day -1) and Day 7, 15

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Day 7	-0.500 (8.1296)	9.200 (8.2280)	4.400 (7.4027)	0.556 (5.2941)	4.667 (4.0620)	1.400 (7.0269)	-0.769 (6.2471)
Day 15	0.083 (3.1176)	0.250 (6.3443)	9.200 (3.1937)	-0.444 (8.2932)	4.889 (7.4237)	0.000 (8.8034)	1.846 (9.1364)

12. Primary Outcome

Title	Number of Bowel Movements (Stool Frequency) as Rated Using the Bristol Stool Form Scale (BSFS) Across Days 1 to 14
Description	The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Time Frame	Up to Day 15 (administered after every in-house bowel movement)

Outcome Measure Data

Analysis Population Description
Safety population

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID	Run-in Only
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.	Participants were received open label metformin 850 mg tablet BID during run-in period, but were withdrawn prior to randomization. Participants swallowed the whole tablet with 240 mL of water and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13	0
Mean (Standard Deviation) [Count of bowel movements]	15.2 (9.29)	28.2 (17.47)	38.4 (10.74)	35.0 (18.49)	37.3 (30.72)	35.9 (21.67)	15.0 (10.96)

13. Primary Outcome

Title	Number of Events With the Rating on Quality of Stools as Rated Using the BSFS Across Days 1 to 14
Description	The site staff classified participant's stools and record the date and time of occurrence after any bowel movement that occurs while participants were in residence in the clinic. BSFS is scale between type 1-7, it measured the shape of the stool, type 1: separate hard lumps, like nuts; type 2: sausage shaped but lumpy; type 3: like a sausage or snake but with cracks on its surface; type 4: like a sausage or snake, smooth and soft; type 5: soft blobs with clear cut edges; type 6: fluffy pieces with ragged edges, a mushy stool and type 7: watery, no solid pieces. Participants were discharged after they have had at least one bowel movement after the Day 14 dosing and after the investigator/designee had reviewed the Day 15 end of study questions.
Time Frame	Up to Day 15 (administered after every in-house bowel movement)

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed. For each BSFS scale rating the "Number of Participants Analyzed" represents the number of participants reporting that rating not the number evaluated.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
BSFS scale rating, 1 event : Events	2	1	1	2
BSFS scale rating, 2 events : Events	6	2	1	10
BSFS scale rating, 3 events : Events	28	4	1	6	5	36
BSFS scale rating, 4 events : Events	56	7	18	19	21	24	41
BSFS scale rating, 5 events : Events	30	2	8	26	9	30	26
BSFS scale rating, 6 events : Events	59	81	113	181	250	201	70
BSFS scale rating, 7 events : Events	16	51	47	86	50	98	10

14. Primary Outcome

Title	Number of Participants With Gastrointestinal Tolerability Assessments as Rated Using the Gastrointestinal Symptom Rating Scale (GSRS; With Worsening Symptoms >=2 Levels)
Description	GSRS is a rating scale consisting of 15 items. Each item was scored from 1: no discomfort at all, 2: minor discomfort, 3: mild discomfort, 4: moderate discomfort, 5: moderately severe discomfort, 6: severe discomfort, 7: very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 1 to 7; a score of 1 indicates that no symptoms are present, and a score of 7 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. There were 5 defined syndrome scores and 1 overall score that was derived by computing the mean of the scores for specific subsets of questions as indicated below: abdominal pain (1, 4, 5); reflux syndrome (2, 3); diarrhea syndrome (11, 12, 14); indigestion syndrome (6, 7, 8, 9); constipation syndrome (10, 13, 15) and overall GSRS (1-15). The data is presented for participants with worsening of symptoms in >=2 levels.
Time Frame	Day 7 and 14

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Pain/discomfort in upper abdomen, Day 7	0 0%	0 0%	2 40%	2 22.2%	0 0%	0 0%	0 0%
Heartburn, Day 7	0 0%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Acid reflux, Day 7	0 0%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Hunger pains, Day 7	0 0%	0 0%	1 20%	0 0%	1 11.1%	1 10%	0 0%
Nausea, Day 7	1 7.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%
Rumbling, Day 7	1 7.7%	0 0%	2 40%	0 0%	1 11.1%	2 20%	0 0%
Bloated, Day 7	2 15.4%	0 0%	1 20%	1 11.1%	0 0%	3 30%	0 0%
Burping, Day 7	1 7.7%	0 0%	1 20%	0 0%	0 0%	2 20%	0 0%
Passing gas or flatus, Day 7	1 7.7%	1 20%	1 20%	1 11.1%	0 0%	2 20%	0 0%
Constipation, Day 7	1 7.7%	0 0%	3 60%	4 44.4%	3 33.3%	0 0%	0 0%
Diarrhea, Day 7	0 0%	0 0%	2 40%	3 33.3%	4 44.4%	4 40%	0 0%
Loose stools, Day 7	1 7.7%	0 0%	3 60%	4 44.4%	3 33.3%	3 30%	0 0%
Hard stools, Day 7	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%
Urgent need to have bowel movement, Day 7	1 7.7%	0 0%	2 40%	1 11.1%	2 22.2%	2 20%	0 0%
Sensatn not complete empty bowels, Day 7	0 0%	0 0%	2 40%	2 22.2%	3 33.3%	2 20%	0 0%
Abdominal pain, Day 7	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Reflux syndrome, Day 7	0 0%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Indigestion syndrome, Day 7	1 7.7%	0 0%	1 20%	0 0%	0 0%	2 20%	0 0%
Constipation syndrome, Day 7	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Diarrhea syndrome, Day 7	0 0%	0 0%	2 40%	3 33.3%	2 22.2%	2 20%	0 0%
Overall GSRS, Day 7	0 0%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Pain/discomfort in upper abdomen, Day 14	1 7.7%	1 20%	2 40%	1 11.1%	1 11.1%	1 10%	1 7.7%
Heartburn, Day 14	1 7.7%	0 0%	2 40%	0 0%	0 0%	0 0%	0 0%
Acid reflux, Day 14	1 7.7%	1 20%	1 20%	0 0%	0 0%	1 10%	0 0%
Hunger pains, Day 14	0 0%	0 0%	2 40%	2 22.2%	0 0%	2 20%	0 0%
Nausea, Day 14	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Rumbling, Day 14	1 7.7%	1 20%	2 40%	1 11.1%	0 0%	2 20%	0 0%
Bloated, Day 14	2 15.4%	1 20%	2 40%	1 11.1%	0 0%	3 30%	00 0%
Burping, Day 14	1 7.7%	1 20%	1 20%	0 0%	0 0%	2 20%	0 0%
Passing gas or flatus, Day 14	0 0%	1 20%	2 40%	2 22.2%	0 0%	2 20%	0 0%
Constipation, Day 14	0 0%	1 20%	1 20%	0 0%	0 0%	2 20%	0 0%
Diarrhea, Day 14	1 7.7%	0 0%	4 80%	3 33.3%	2 22.2%	5 50%	0 0%
Loose stools, Day 14	1 7.7%	1 20%	3 60%	2 22.2%	3 33.3%	3 30%	0 0%
Hard stools, Day 14	0 0%	0 0%	2 40%	0 0%	0 0%	1 10%	0 0%
Urgent need to have bowel movement, Day 14	1 7.7%	1 20%	4 80%	2 22.2%	3 33.3%	3 30%	0 0%
Sensation not complete empty bowels, Day 14	0 0%	0 0%	3 60%	2 22.2%	3 33.3%	2 20%	0 0%
Abdominal pain, Day 14	0 0%	0 0%	1 20%	0 0%	0 0%	0 0%	0 0%
Reflux syndrome, Day 14	1 7.7%	0 0%	1 20%	0 0%	0 0%	1 10%	0 0%
Indigestion syndrome, Day 14	0 0%	1 20%	1 20%	1 11.1%	0 0%	2 20%	0 0%
Constipation syndrome, Day 14	0 0%	0 0%	2 40%	0 0%	0 0%	2 20%	0 0%
Diarrhea syndrome, Day 14	0 0%	0 0%	3 60%	2 22.2%	1 11.1%	3 30%	0 0%
Overall GSRS, Day 14	0 0%	0 0%	1 20%	1 11.1%	0 0%	2 20%	0 0%

15. Primary Outcome

Title	Number of Participants With Fecal Occult Blood Monitoring for Symptomatic or Visible Gastrointestinal Bleeding or Asymptomatic Occult Bleeding
Description	Testing cards were provided to participants for assessments. Participants with abnormal not clinically significant and abnormal clinically significant is presented. The Day -1 sample was obtained any time starting Day -2 and prior to GSK2330672 dosing on Day 1. The Day 14 sample was collected any time after dosing on Day 14 and prior to discharge on Day 15.
Time Frame	Up to Day 15

Outcome Measure Data

Analysis Population Description
Safety population

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID	Run-in Only
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.	Participants were received open label metformin 850 mg tablet BID during run-in period, but were withdrawn prior to randomization. Participants swallowed the whole tablet with 240 mL of water and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13	6
Abnormal not clinically significant	0 0%	1 20%	1 20%	0 0%	0 0%	1 10%	1 7.7%	0 0%
Abnormal clinically significant	0 0%	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%	2 33.3%

16. Secondary Outcome

Title	PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-maximum Observed Concentration (Cmax)
Description	The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Statistics for geometric least square mean provided.
Time Frame	Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14

Outcome Measure Data

Analysis Population Description
The PK population was used which was defined as participants from the safety population who had plasma metformin, sitagliptin, and/or GSK2330672 PK parameter estimates from any portion of the study. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.
Measure Participants	12	4	5	9	8	9	13
Geometric Least Squares Mean (Geometric Coefficient of Variation) [Nanograms per milliliter (ng/mL)]	1102.2 (26.92)	1289.3 (41.81)	1219.9 (23.76)	1160.0 (18.64)	1378.8 (22.77)	1376.6 (21.70)	1223.5 (27.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 90% 0.92 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and confidence interval (CI) for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90% 0.89 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 90% 0.87 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90% 1.03 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90% 1.04 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an analysis of variance (ANOVA) model of log-transformed values.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90% 0.94 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

17. Secondary Outcome

Title	PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-time of Occurrence of Cmax (Tmax)
Description	The time at which Cmax observed was determined directly from the raw concentration-time data.
Time Frame	Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14

Outcome Measure Data

Analysis Population Description
PK population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	12	4	5	9	8	9	13
Median (Full Range) [Hour]	1.510	1.000	1.000	1.050	1.750	1.500	2.050

18. Secondary Outcome

Title	PK Parameters for Metformin Steady State PK Parameters When Co-dosed With GSK2330672, Sitagliptin or Placebo-area Under the Concentration-time Curve Over the Dosing Interval of 10 Hours (AUC[0-10])
Description	PK population. Only those participants available at the specified time points were analyzed.
Time Frame	Fasting pre-dose (within 15 minutes of dose), 30 minutes, 1, 1.5, 2, 3, 4 (pre-lunch), 5.5, 8, 10 hours (pre-dinner) on Day 14

Outcome Measure Data

Analysis Population Description
PK population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	12	4	5	9	8	9	13
Geometric Mean (Geometric Coefficient of Variation) [Hour×ng/mL]	6805.8 (19.70)	5982.0 (34.72)	7066.2 (25.80)	7066.5 (16.09)	8090.5 (33.06)	8375.3 (32.78)	8425.4 (28.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 90% 0.68 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 90% 0.82 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 90% 0.85 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 90% 0.97 to 1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 90% 1.01 to 1.49
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments	Each GSK2330672 dose level was compared to placebo using an ANOVA model following log-transformation.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Ratio
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 90% 1.04 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mean and CI for the difference in least squares means (Active-Placebo) are back-transformed to form the point estimate and associated CI for the ratio of geometric means.

19. Secondary Outcome

Title	Ratio to Baseline in Fasting Low-density Cholesterol (LDL) Cholesterol, High-density Cholesterol (HDL) Cholesterol, Total Cholesterol, Non-HDL Cholesterol and Triglycerides
Description	Data for fasting low-density cholesterol (LDL) cholesterol, high-density cholesterol (HDL) cholesterol, total cholesterol, non-HDL cholesterol and triglycerides is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
Time Frame	Baseline (pre-dose Day -1) and Day 7, 14

Outcome Measure Data

Analysis Population Description
Safety population. Only those participants available at the specified time points were analyzed.

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Cholesterol, Day 7	0.95 (10.9)	0.99 (12.1)	0.84 (12.4)	0.84 (13.7)	0.74 (11.0)	0.80 (3.7)	0.97 (9.8)
Cholesterol, Day 14	0.95 (13.1)	0.98 (14.2)	0.81 (20.8)	0.83 (18.5)	0.75 (8.8)	0.75 (6.7)	0.92 (11.1)
HDL cholesterol, Day 7	1.00 (7.3)	1.08 (12.8)	1.05 (8.9)	0.97 (8.0)	0.95 (11.4)	1.09 (15.7)	0.97 (9.0)
HDL cholesterol, Day 14	0.99 (6.5)	1.11 (1.5)	1.02 (4.0)	0.97 (8.8)	0.96 (11.4)	1.01 (11.6)	0.97 (10.2)
LDL cholesterol, Day 7	0.97 (14.6)	0.89 (6.4)	0.77 (21.1)	0.73 (21.5)	0.58 (21.2)	0.71 (6.5)	1.00 (10.5)
LDL cholesterol, Day 14	0.94 (17.6)	0.80 (4.2)	0.69 (23.1)	0.72 (23.7)	0.60 (15.0)	0.67 (16.3)	0.92 (15.3)
Non-HDL Cholesterol, Day 7	0.93 (13.8)	0.96 (12.6)	0.78 (18.2)	0.80 (18.2)	0.65 (12.0)	0.73 (5.1)	0.98 (11.9)
Non-HDL Cholesterol, Day 14	0.94 (17.7)	0.94 (17.5)	0.74 (29.7)	0.78 (23.7)	0.67 (7.2)	0.68 (8.6)	0.90 (15.1)
Triglycerides, Day 7	0.85 (20.6)	1.07 (51.2)	0.93 (18.8)	1.11 (24.5)	0.98 (19.8)	0.93 (16.3)	0.79 (32.7)
Triglycerides, Day 14	0.85 (23.0)	1.21 (63.3)	0.96 (35.8)	1.07 (34.3)	1.00 (16.6)	1.00 (23.7)	0.74 (34.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95% 0.91 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.78 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95% 0.78 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95% 0.68 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.76 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95% 0.92 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, cholesterol

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95% 0.95 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95% 0.94 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95% 0.88 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.89 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95% 0.98 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.90 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, HDL cholesterol

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.80 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95% 0.65 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.64 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95% 0.51 to 0.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95% 0.62 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.89 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, LDL cholesterol

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95% 0.88 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.71 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95% 0.74 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95% 0.59 to 0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.68 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.92 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, non-HDL cholesterol

Statistical Analysis 25

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 95% 0.97 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 26

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95% 0.90 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 27

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95% 1.06 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 28

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95% 0.96 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 29

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95% 0.93 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 30

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95% 0.79 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, triglycerides

Statistical Analysis 31

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95% 0.86 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 32

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95% 0.73 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 33

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.73 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 34

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.66 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 35

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.69 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 36

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95% 0.84 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, cholesterol

Statistical Analysis 37

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.09
	Confidence Interval	(2-Sided) 95% 0.99 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 38

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.93 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 39

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.90 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 40

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95% 0.92 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 41

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95% 0.94 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 42

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.92 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, HDL cholesterol

Statistical Analysis 43

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.85
	Confidence Interval	(2-Sided) 95% 0.69 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 44

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.58 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 45

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.62 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 46

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.60
	Confidence Interval	(2-Sided) 95% 0.50 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 47

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95% 0.59 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 48

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95% 0.81 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, LDL cholesterol

Statistical Analysis 49

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95% 0.80 to 1.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 50

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.64 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 51

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.67 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 52

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95% 0.55 to 0.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 53

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.60 to 0.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 54

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95% 0.80 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, non-HDL cholesterol

Statistical Analysis 55

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.42
	Confidence Interval	(2-Sided) 95% 1.01 to 2.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

Statistical Analysis 56

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95% 0.94 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

Statistical Analysis 57

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95% 0.98 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

Statistical Analysis 58

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95% 0.95 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

Statistical Analysis 59

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95% 0.96 to 1.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

Statistical Analysis 60

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95% 0.72 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, triglycerides

20. Secondary Outcome

Title	Ratio to Baseline in Fasting Apolipoprotein B
Description	Data for fasting apolipoprotein B is presented. Participants withdrawing early were excluded. Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.
Time Frame	Baseline (pre-dose Day -1) and Day 7, 14

Outcome Measure Data

Analysis Population Description
Safety population

Arm/Group Title	Placebo	GSK2330672 10 mg BID	GSK2330672 20 mg BID	GSK2330672 30 mg BID	GSK2330672 60 mg BID	GSK2330672 90 mg BID	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13	5	5	9	9	10	13
Day 7	0.97 (10.6)	0.95 (5.9)	0.78 (13.9)	0.81 (13.1)	0.69 (12.0)	0.76 (3.8)	0.96 (10.3)
Day 14	0.93 (14.2)	0.85 (6.7)	0.75 (19.0)	0.78 (19.6)	0.67 (14.9)	0.69 (9.3)	0.88 (15.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95% 0.87 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95% 0.71 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95% 0.74 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95% 0.63 to 0.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95% 0.70 to 0.85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95% 0.89 to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 7, apolipoprotein B

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 10 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95% 0.77 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 20 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.68 to 0.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 30 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95% 0.70 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 60 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95% 0.58 to 0.77
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK2330672 90 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.64 to 0.83
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Placebo, Sitagliptin 50 mg BID
	Comments	An estimation approach was used.
	Type of Statistical Test	Superiority or Other
	Comments	Results were based on an ANCOVA model: Log(post-Baseline) - Log(Baseline) = Log(Baseline) + treatment + concomitant use of lipid lowering drugs.

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95% 0.80 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Comparison for Day 14, apolipoprotein B

21. Secondary Outcome

Title	Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Cmax Following the First and Second Sitagliptin Doses
Description	The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Cmax1 and Cmax2).
Time Frame	Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14

Outcome Measure Data

Analysis Population Description
PK population.

Arm/Group Title	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13
Cmax 1	238.2 (26.20)
Cmax 2	188.5 (25.34)

22. Secondary Outcome

Title	Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-Tmax Following the First and Second Sitagliptin Doses
Description	The time at which Cmax was observed by determining directly from the raw concentration-time data following the first and second dose of sitagliptin on Day 14 (Tmax1 and Tmax2). If data permits, Tmax2 was defined as the time of Cmax following the second dose of sitagliptin.
Time Frame	Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner), 13 and 14 hours (bed time) on Day 14

Outcome Measure Data

Analysis Population Description
PK population.

Arm/Group Title	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13
Tmax 1	2.000
Tmax 2	3.050

23. Secondary Outcome

Title	Sitagliptin Steady State PK Parameters When Co-dosed With Metformin-AUC(0-10)
Description	The AUC(0-10) following the first dose and prior to the second dose of sitagliptin was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations.
Time Frame	Fasting pre-dose (within 15 minutes of dose), 1, 2, 3, 4 (pre-lunch), 10 (pre-dinner) on Day 14

Outcome Measure Data

Analysis Population Description
PK population.

Arm/Group Title	Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
Measure Participants	13
Geometric Mean (Geometric Coefficient of Variation) [Hour×ng/mL]	1473.5 (22.45)

Adverse Events

	Placebo		GSK2330672 10 mg BID		GSK2330672 20 mg BID		GSK2330672 30 mg BID		GSK2330672 60 mg BID		GSK2330672 90 mg BID		Sitagliptin 50 mg BID
Time Frame	AEs and SAEs were collected from run-in period until the follow-up contact (7-10 days after discharge). SAEs and non-SAE were reported from treatment period only (up to 14 days).
Adverse Event Reporting Description	Safety population used for assessment of safety results.

Arm/Group Title	Placebo		GSK2330672 10 mg BID		GSK2330672 20 mg BID		GSK2330672 30 mg BID		GSK2330672 60 mg BID		GSK2330672 90 mg BID		Sitagliptin 50 mg BID
Arm/Group Description	Participants were randomized to receive matching placebo solution of GSK2330672 orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The matching placebo solution of GSK2330672, was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive solution of GSK2330672 10 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive solution of GSK2330672 20 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued received metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive solution of GSK2330672 30 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive solution of GSK2330672 60 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive solution of GSK2330672 90 mg orally BID for 14 days. Participants drank the contents of dosing bottle (45 mL) followed by 2×50 mL rinses of bottle and then an additional 95 mL water for a total volume of 240 mL consumed. The solution of GSK2330672 (2 mg/mL), was prepared by clinical staff pharmacists after reconstitution of GSK2330672 powder with phosphate buffer into amber glass bottles for administration. All dosing treatments, bottle rinses and additional water was consumed within a 15 minute period. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the whole metformin tablet with 240 mL of water and were instructed to avoid chewing or crushing.		Participants were randomized to receive sitagliptin 50 mg tablet orally BID for 14 days. Participants continued to receive metformin 850 mg tablet BID throughout the study (run-in and treatment period). Participants swallowed the both whole tablets of sitagliptin and metfornin with 240 mL of water each and were instructed to avoid chewing or crushing.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Serious Adverse Events
	Placebo		GSK2330672 10 mg BID		GSK2330672 20 mg BID		GSK2330672 30 mg BID		GSK2330672 60 mg BID		GSK2330672 90 mg BID		Sitagliptin 50 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Cardiac disorders
Arrhythmia supraventricular	0/13 (0%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		GSK2330672 10 mg BID		GSK2330672 20 mg BID		GSK2330672 30 mg BID		GSK2330672 60 mg BID		GSK2330672 90 mg BID		Sitagliptin 50 mg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/13 (69.2%)		3/5 (60%)		5/5 (100%)		5/9 (55.6%)		8/9 (88.9%)		8/10 (80%)		8/13 (61.5%)
Ear and labyrinth disorders
Ear discomfort	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Eye disorders
Ocular hyperaemia	0/13 (0%)		0/5 (0%)		0/5 (0%)		1/9 (11.1%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Scleral hyperaemia	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Gastrointestinal disorders
Diarrhoea	4/13 (30.8%)		2/5 (40%)		5/5 (100%)		2/9 (22.2%)		7/9 (77.8%)		6/10 (60%)		2/13 (15.4%)
Abdominal pain	2/13 (15.4%)		1/5 (20%)		2/5 (40%)		2/9 (22.2%)		1/9 (11.1%)		2/10 (20%)		1/13 (7.7%)
Flatulence	1/13 (7.7%)		0/5 (0%)		1/5 (20%)		0/9 (0%)		1/9 (11.1%)		3/10 (30%)		1/13 (7.7%)
Faeces soft	1/13 (7.7%)		0/5 (0%)		0/5 (0%)		2/9 (22.2%)		1/9 (11.1%)		2/10 (20%)		0/13 (0%)
Dyspepsia	0/13 (0%)		1/5 (20%)		1/5 (20%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		2/13 (15.4%)
Nausea	1/13 (7.7%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		2/9 (22.2%)		0/10 (0%)		1/13 (7.7%)
Proctalgia	0/13 (0%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		1/10 (10%)		0/13 (0%)
Eructation	1/13 (7.7%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Gastrooesophageal reflux disease	1/13 (7.7%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Vomiting	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		1/10 (10%)		0/13 (0%)
Abdominal discomfort	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Abdominal distension	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Abdominal pain upper	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Gastrointestinal sounds abnormal	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Glossodynia	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Haemorrhoids	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Oral discomfort	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Rectal haemorrhage	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
General disorders
Feeling hot	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Feeling jittery	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Infections and infestations
Viral infection	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		2/9 (22.2%)		0/10 (0%)		0/13 (0%)
Urinary tract infection	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Injury, poisoning and procedural complications
Anal injury	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Skin abrasion	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Investigations
Alanine aminotransferase increased	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Blood pressure increased	0/13 (0%)		0/5 (0%)		0/5 (0%)		1/9 (11.1%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Blood triglycerides increased	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Liver function test abnormal	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		1/10 (10%)		0/13 (0%)
Musculoskeletal discomfort	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Musculoskeletal pain	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Myalgia	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Pain in extremity	0/13 (0%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		0/13 (0%)
Nervous system disorders
Headache	2/13 (15.4%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		2/9 (22.2%)		1/10 (10%)		0/13 (0%)
Dizziness	0/13 (0%)		1/5 (20%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Paraesthesia	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/13 (0%)		0/5 (0%)		1/5 (20%)		1/9 (11.1%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Oropharyngeal pain	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Skin and subcutaneous tissue disorders
Pruritus	1/13 (7.7%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		1/9 (11.1%)		0/10 (0%)		0/13 (0%)
Rash	1/13 (7.7%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)
Dermatitis contact	0/13 (0%)		0/5 (0%)		0/5 (0%)		0/9 (0%)		0/9 (0%)		0/10 (0%)		1/13 (7.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT02202161

Other Study ID Numbers:

201351

First Posted:

Jul 28, 2014

Last Update Posted:

Nov 6, 2017

Last Verified:

Aug 1, 2017