A Study in Type 2 Diabetics of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics

Study Overview
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Brief Summary
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The purpose of this study is to see if GSK1292263 is safe and well-tolerated when administered to type 2 diabetics, and to get preliminary information about whether it may be effective in the treatment of type 2 diabetes.

Detailed Description
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Data from this study will be used to assess the potential of GSK1292263 as a treatment for T2DM, and will aid the design and dose selection of future studies of longer duration in T2DM subjects that will evaluate GSK1292263 alone or in combination with other anti-diabetic drugs.

Official Title
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A Study in Type II Diabetic Subjects of Single and Multiple Doses of Orally Administered GSK1292263 to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the Compound Alone and When Co-administered With Sitagliptin or Metformin

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: GSK1292263
* Drug: GSK1292263 matching placebo
* Drug: Sitagliptin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, 18 - 60 years of age, inclusive, at the time of signing the informed consent. A female subject is eligible to participate if she is of non-childbearing potential, defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. FSH and estradiol levels will be checked at Screening for postmenopausal women. Simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40pg/ml (<140pmol/L) is confirmatory. Except as noted elsewhere, subjects should have no significant known medical conditions other than T2DM, as determined by a responsible physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECGs. A subject with a clinical abnormality or laboratory parameters that meets exclusion criteria but is outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. BMI (body mass index) within the range 22-35 kg/m2, inclusive. Part A - T2DM diagnosed by American Diabetes Association criteria at least 3 months prior to Screening with: Currently controlled by diet and exercise. Fasting plasma glucose (FPG) level <= 250mg/dL at the Screening visit FPG level <= 250mg/dL on Day -1 HbA1c between 6.5 and 11%, inclusive, at Screening visit For Parts B and C, T2DM diagnosed by American Diabetes Association criteria at least 3 months prior to Screening with: T2DM currently controlled by diet and exercise, or, if on medication, subjects must be treating their T2DM using one of the following regimens: Metformin as monotherapy Sulfonylurea as monotherapy Metformin and sulfonylurea in combination, if both components are being administered at doses that are half their maximum dose or less DPP-IV inhibitors, either as monotherapy or in combination with other agent(s) on this list at half maximal dose or less Exenatide, either as monotherapy or in combination with other agent(s) on this list at half maximal dose or less For subjects that are being screened for Parts B and C, all doses of anti-diabetic medication must have been stable for at least 3 months prior to Screening, and the subject must be willing to wash out from their anti-diabetic medications from Day -7 through post-last-dose of Period 2 (Part B) or Day -7 through Day 15 (Part C). Fasting plasma glucose (FPG) level <= 220mg/dL at the Screening visit FPG level <= 250mg/dL on Day -1 HbA1c between 7 and 11%, inclusive, at Screening visit Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: Has any of the following laboratory abnormalities: Positive pre-study Hepatitis B surface antigen or positive Hepatitis C, result within 3 months of screening. Positive test for HIV antibody. History of uncorrected thyroid dysfunction or an abnormal thyroid function test assessed by TSH at Screening. (NOTE: subjects with hypothyroidism on a stable dose of thyroid replacement therapy for at least 3 months prior to Screening and who have a screening thyroid stimulating hormone (TSH) within the normal range may participate.) ALT and/or AST > 2 times the upper limit of normal at screening. Fasting triglycerides > 450mg/dL at screening. Total Bilirubin > 1.5 times the upper limit of normal at screening. For females a haemoglobin < 11.5 g/dL, and for males a hemoglobin < 12.5 g/dL. Hemoglobin < 11g/dL(A female subject with haemoglobin between 10g/dL and 11.5 g/dL, or a male subject with haemoglobin between 10g/dL and 12.5 g/dLmay be enrolled only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk to the subject and will not interfere with the study procedures). A positive pre-study drug/urine screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. A pre-study urine cotinine screen indicating use of tobacco/ nicotine containing products. If female is pregnant or has a positive pregnancy test Significant renal disease as manifested by one or more of the following: Creatinine clearance <60mL/min. (estimated from serum creatinine (SCr) and demographic data using the MDRD calculation): To calculate estimated GFR (mL/min/1.73m2) manually: =186 x (SCr in mg/dL)-1.154 x (age)-0.203 x (0.742 if female) x (1.210 if African-American) =exp (5.228-1.154 x ln (SCr)-0.203x ln(age)-(0.299 if female) + (0.192 if African American)) (A link to a validated MDRD calculator on the internet is provided in the SRM.) Urine protein/creatinine (mg of protein/mg of creatinine) ratio >2.5; or urine albumin concentration >300mg/g of creatinine). Known loss of a kidney either by surgical ablation, injury, or disease. Significant ECG abnormalities, defined as follows: Heart Rate < 50 and >100bpm PR Interval <120 and > 220ms QRS duration < 70 and >120ms QTC Interval (Bazett)* > 450ms Or, has clinically significant rhythm abnormalities identified during 24-hour Screening Holter assessment. Subjects with Left Bundle Branch Block are excluded from the study. Subjects with partial Right Bundle Branch Block may be considered for inclusion following consultation with the GSK Medical Monitor. Subjects with WPW syndrome are excluded from the study. *Note that if ECG abnormalities are identified, the ECG should be repeated two more times (with 5 minutes between ECG readings) and the average of the 3 values used to determine eligibility. Systolic pressure > 150mmHg or <80mmHg or diastolic blood pressure > 95mmHg or <60mmHg at screening. Blood pressure assessments may be repeated once if needed, allowing adequate time for subject to rest. Previous use of insulin as a treatment within 3 months of Screening, or for >2 weeks when used for acute illness in the last 12 months prior to Screening, or if used for more than 1 year when associated with gestational diabetes mellitus. Has a history of any of the following conditions: Clinically significant symptoms of gastroparesis Cholelithiasis or obstructive or inflammatory gallbladder disease within 3 months prior to Screening Gastrointestinal disease that could affect fat or bile acid absorption, including inflammatory bowel disease, chronic diarrhea, Crohn's or malabsorption syndromes within the past year Gastrointestinal surgery Chronic or acute pancreatitis History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360mL) of beer, 5 ounces (150mL) of wine or 1.5 ounces (45mL) of 80 proof distilled spirits. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening. Has participated in a clinical trial and has received a drug or a new chemical entity within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Is taking prohibited medications. See Section 9.3 for a detailed list of prohibited medications. Note also: The use of anti-diabetic agents other than those listed in Inclusion #7 is reason for exclusion and subjects will not be allowed to wash off of unapproved anti-diabetic medications in order to qualify for participation in this study. Subjects must wash out from the following medications during the 7-day period prior to first dose, and must remain off these medications through discharge on post-last-dose of Period 2 (Part B) or Day 15 (Part C): all anti-diabetic medications specified in Inclusion #7, all statin agents, fat absorption blocking agents, bile acid sequestrants. Fibrates must be washed out for a 14-day period prior to first dose. Vitamins, herbal and dietary supplements (including St John's Wort) are prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication and through discharge. Unwilling to abstain from Caffeine-or xanthine-containing products for 24 hours prior to dosing until post-last-dose of Period 5 (Part A), post-last-dose of Period 2 (Part B) or Day -7 through Day 15 (Part C). Use of illicit drugs or nicotine-containing products Alcohol for 24 hours prior to dosing until post-last-dose of Period 5 (Part A), post-last-dose of Period 2 (Part B) or Day -7 through Day 15 (Part C). Consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication until collection of the final pharmacokinetic blood samples. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. This includes sensitivity to heparin or heparin-induced thrombocytopenia, if heparin will be used to maintain catheter patency. Where participation in the study would result in donation of blood in excess of approximately 500mL within a 56 day period. Subject is either an immediate family member of a participating investigator, study coordinator, employee of an investigator; or is a member of the staff conducting the study. Unwillingness or inability to follow the procedures outlined in the protocol. Subject is mentally or legally incapacitated.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br>Part A (Cohort 1) is a single-blind, randomized, placebo-controlled, 5-period crossover in which drug naïve T2DM subjects will receive escalating doses of GSK1292263 in each of 3 periods and placebo and open-label sitagliptin in the other 2 periods. The sequence will be randomized, but will maintain the low, medium and high dose order for GSK1292263. | Drug: GSK1292263<br>* GSK1292263 is an immediate-release round, white, film-coated tablet provided in 3 strengths, 25mg, 75mg and 200mg being developed for the treatment of type 2 diabetes.<br>Drug: GSK1292263 matching placebo<br>* Matching placebo to active drug GSK1292263<br>Drug: Sitagliptin<br>* Sitagliptin (Januvia) 100mg tablets are beige, round, film-coated tablets with 277 on one side.<br>* Other names: Januvia;|
| Experimental: Part B<br>Part B (Cohort 2) is a single-blind, randomized, 2-period study in which T2DM subjects will receive a single dose of GSK1292263, fasted or fed. | Drug: GSK1292263<br>* GSK1292263 is an immediate-release round, white, film-coated tablet provided in 3 strengths, 25mg, 75mg and 200mg being developed for the treatment of type 2 diabetes.<br>|
| Experimental: Part C<br>Part C (Cohort 3, optional Cohort 4) is a single-blind, randomized, placebo-controlled, 5-arm study of 14 days of dosing with GSK1292263, placebo or open-label sitagliptin. An optional Cohort 4 may be enrolled to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK1292263 when dosed in a BID regimen. | Drug: GSK1292263<br>* GSK1292263 is an immediate-release round, white, film-coated tablet provided in 3 strengths, 25mg, 75mg and 200mg being developed for the treatment of type 2 diabetes.<br>Drug: GSK1292263 matching placebo<br>* Matching placebo to active drug GSK1292263<br>Drug: Sitagliptin<br>* Sitagliptin (Januvia) 100mg tablets are beige, round, film-coated tablets with 277 on one side.<br>* Other names: Januvia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Up to Week 10 | 
| Part A: Number of Participants With Abnormal Hematology Parameters of Potential Clinical Importance (PCI) | Hematology parameters included platelet count, red blood cell (RBC) count, mean corpuscular volume (MCV), total neutrophils, white blood cell count (WBC; absolute), mean corpuscular hemoglobin (MCH), lymphocytes, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit, reticulocytes and basophils. It was assessed on Screening, Day -1, Day 2 (of each treatment period) and Follow-up (7 to 10 days after final discharge). Only those parameters (hemoglobin, high) for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 10 | 
| Part A: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI | Clinical chemistry parameters included blood urea nitrogen (BUN), potassium, aspartate aminotransferase (AST), total and direct bilirubin, creatinine, chloride, alanine aminotransferase (ALT), uric acid, glucose fasting, gamma glutamyltransferase (GGT), albumin, sodium, magnesium, phosphorus inorganic, calcium, total carbon dioxide (CO2), alkaline phosphatase (ALP), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, free fatty acid (non-esterified fatty acids; [NEFA]), high-density lipoprotein (HDL) cholesterol and total protein. It was assessed on Screening, Day -1, Day 2 (of each treatment period) and Follow-up (7 to 10 days after final discharge). Only those parameters for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 10 | 
| Part A: Number of Participants With Abnormal Electrocardiogram (ECG) Findings | Twelve-lead ECGs was obtained in a supine position at each time point during the study using an ECG machine that automatically measured PR, QRS, QT and QTc intervals (QT duration corrected for heart rate by Bazett's formula [QTcB] and Fridericia's formula [QTcF]). Participants with abnormal clinically significant ECG findings is presented. It was assessed on Screening, Day 1 at pre-dose, 1, 2, 3, 4, 6, 10, 16, 24 hours and Follow-up (7 to 10 days after final discharge). | Up to Week 10 | 
| Part A: Number of Participants With Abnormal Vital Signs of PCI | Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate measurements were recorded at each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Participants with abnormal clinically significant vital signs findings is presented. It was assessed on Screening, Day -1, 1, 2 (pre-dose, 1, 3, 4, 6, 10, 16 and 24 hours of each treatment period) and Follow-up (7 to10 days after final discharge). | Up to Week 10. | 
| Part A: Summary of Maximum Plasma Concentration (Cmax) | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Blood samples for the determination of PKs was collected at on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period | 
| Part A: Summary of Time to Maximum Concentration (T-max) and Lag Time Before Observation of Drug Concentration in Sampled Matrix (T-lag) | The time at which Cmax was observed was determined directly from the raw concentration-time data. The lag time before observation of drug concentrations in sample matrix determined as the time of the sample preceding the first quantifiable concentration. Blood samples for the determination of PK was collected on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period | 
| Part A: Summary of Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) and Area Under the Concentration-time Curve From Zero (Pre-dose) to 24 Hours (AUC0-24) | The AUC 0-24 and AUC 0-t determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples for the determination of PK was collected at on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 14 and 24 hours on Day 1 of each treatment period | 
| Part C: Number of Participants With AEs and SAEs | An AE was defined as any untoward MO in a participant temporally associated with the use of a 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. | Up to Week 7 | 
| Part C: Number of Participants With Abnormal Hematology Parameters of PCI | Hematology parameters included platelet count, RBC count, MCV, total neutrophils, WBC absolute, MCH, lymphocytes, MCHC, monocytes, hemoglobin, eosinophils, hematocrit, reticulocytes and basophils. It was assessed on Screening, Day -2 (can be non-fasting) and prior to breakfast (early in the morning, fasting) on Days 1, 7 and 14, and on Day 15 prior to checkout, (=24 hours post-dose) of each treatment period and Follow-up (7 to 10 days after final discharge). Only those parameters for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 7 | 
| Part C: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI | Clinical chemistry parameters included BUN, potassium, AST, total and direct bilirubin, creatinine, chloride, ALT, uric acid, glucose fasting, GGT, albumin, sodium, magnesium, phosphorus inorganic, calcium, total CO2, ALP, triglycerides, total cholesterol, LDL cholesterol, free fatty acid (NEFA), HDL cholesterol and total protein. It was assessed on Screening, Day -2 (can be non-fasting) and prior to breakfast (early in the morning, fasting) on Days 1, 7 and 14, and on Day 15 prior to checkout, (=24 hours post-dose) of each treatment period and Follow-up (7 to 10 days after final discharge). Only those parameters for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 7 | 
| Part C: Number of Participants With Significant ECG Abnormalities | Twelve-lead ECGs was obtained in a supine position at each time point during the study using an ECG machine that automatically measured PR, QRS, QT and QTc intervals (QTcB and QTcF). Participants with abnormal clinically significant ECG findings is presented. It was assessed on Screening, on Day -1, 1, 7, 13 and 14 pre-breakfast dose (fasting) and at 1, 3, 6, 9, 12 and 24 hours of each treatment period and Follow-up (7 to 10 days after final discharge). | Up to Week 7 | 
| Part C: Number of Participants With Abnormal Vital Signs of PCI | SBP, DBP and pulse rate measurements were recorded at each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Participants with abnormal clinically significant vital signs findings is presented. It was assessed on Screening, on Days -1 to 14 in a fasting state early in the morning (prior to morning dosing on days 1-14) and at Follow-up. On Days 1, 7, 13 and 14, it was also taken at 1, 3, 6, 9, 12 and 24 hours after the morning dose each treatment period and Follow-up (7 to 10 days after final discharge). | Up to Week 7 | 
| Part C: Summary of Plasma Cmax | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post-breakfast), 1, 2, 4 (= pre-lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of T-max and T-lag | The time at which Cmax was observed was determined directly from the raw concentration-time data. The lag time before observation of drug concentrations in sample matrix determined as the time of the sample preceding the first quantifiable concentration. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post-breakfast), 1, 2, 4 (= pre-lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of AUC0-10, AUC0-12 and AUC0-24 | The AUC0-10, AUC0-12 and AUC0-24 determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For QD and BID dosing regimens on Day 7, blood samples were collected at pre-dose (=post- breakfast), 1, 2, 4 (=pre lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of Accumulation Ratio (Ro) | Ro was derived as follows: Ro = Day 13 (AUC0-24)/Day 1 (AUC0-24) for once daily dosing; Ro = Day 13 AM (AUC0-10)/Day 1 AM (AUC0-10) for BID dosing and Ro = Day 13 (AUC0-24)/Day 1 (AUC0-24) for BID dosing. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post-breakfast), 1, 2, 4 (= pre-lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. Data presented for Day 13 and Day 14. | Days 1, 7, 13 and 14 | 
| Part C: Summary of Time Invariance Ratio (Rs) of AUC0-10 for BID Dose of GSK1292263 | The AUC0-10 determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (=post-breakfast), 1, 2, 4 (=pre lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of Time Invariance Ratio (Rs) of AUC0-24 for Once Daily Dose of GSK1292263 | The AUC0-24 determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (=post-breakfast), 1, 2, 4 (=pre lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of Time Invariance Ratio (Rs) of Cmax | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (=post-breakfast), 1, 2, 4 (=pre lunch), 6, 10 (=immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. Cmax for one participant from 50 BID x 14 day was not analyzed due to positive definite G Matrix. | Days 1, 7, 13 and 14 | 
| Part A: Relationships Between GSK1292263 Drug Exposures and Insulin Sensitivity | Blood samples for the determination of insulin were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. For lunch and evening meal in Part A, samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5 (except breakfast in Part B), 2 and 3 hours. When this results in multiple samples at the same time point, only one sample was collected. The unit of measure is mL/min×1/micro international unit×10^4 (mL/min×1/µIU×10^4). | Day 1 of each treatment period | 
| Part C: Relationships Between GSK1292263 Drug Exposures and Insulin Sensitivity | Blood samples for the determination of insulin were collected fasting pre-breakfast and then pre-morning dose (PD time 0) on Days -1, 13 and 14, and then at 10, 20, 30, 60, 90, 120, 180 min after eating the standardized breakfast meal tolerance test. For lunch (approximately 4 hour post-morning dose) samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5, 2 and 3 hours. For the evening meal (approximately 10 hour post-morning dose), BID dosing groups followed the sequence of sampling, food and dosing as for breakfast (PD sample immediately before meal, eat and then dose), then 0.5, 1, 1.5, 2 and 3 hours post-dinner. A sample was also collected 24 hours post-dose. When this results in multiple samples at the same time point, only one sample was collected (example: 24 hours post first-dose = pre-dose [time 0] for the second dose). | Day -1, 13 and 14 | 
| Part A: Summary of Change From Baseline in Fasted Glucose | Blood samples for the determination of glucose were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. For lunch and evening meal in Part A, samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5 (except breakfast in Part B), 2 and 3 hours. When this results in multiple samples at the same time point, only one sample was collected. Change from Baseline was calculated by subtracting Baseline value from post-Baseline value. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Baseline (Day 1 pre-dose) and Day 1 (24 hours) | 
| Part A: Summary of the AUC 0-13, AUC 0-24, Incremental AUC (iAUC) 0-13 and iAUC 0-24 of Glucose | Blood samples for the determination of glucose were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. For lunch and evening meal in Part A, samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5 (except breakfast in Part B), 2 and 3 hours. When this results in multiple samples at the same time point, only one sample was collected. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the AUC 0-12 and iAUC 0-12 of Glucagon, Glucagon-like Peptide (GLP; Active and Total)-1, C-peptide, Total Glucose-dependent Insulinotropic Peptide (GIP) and Total Peptide Tyrosine-tyrosine (PYY) and AUC 0-13 and iAUC 0-13 of Insulin | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. For lunch and evening meal in Part A, samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5 (except breakfast in Part B), 2 and 3 hours. When this results in multiple samples at the same time point, only one sample was collected. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT AUC (0-3) and iAUC(0-3)-Glucose | Blood samples for the determination of glucose were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT AUC (0-2) and iAUC(0-2)- C-peptide, Total GIP, GLP-1 (Active and Total), Glucagon and Total PYY and AUC 0-3 and iAUC 0-3 of Insulin | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT Derived Parameters: Disposition Index | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. It was calculated by multiplying insulin glucose index with insulin sensitivity index. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT Derived Parameters: Glucose/Insulin and Insulin/Glucose Ratio | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. It was calculated as insulin/glucose ratio was calculated as insulin AUC(0-3]/glucose AUC(0-3) during OGTT, while glucose/insulin ratio was calculated as glucose AUC(0-3)/insulin AUC(0-3) during OGTT. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT Derived Parameters: Insulin Glucose Index | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. It was calculated as insulin (30 min) - insulin (0 min)/glucose (30 min) - glucose (0 min). It was calculated as insulin (30 min) - insulin (0 min)/glucose (30 min) - glucose (0 min). The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part A: Summary of the OGTT Derived Parameters: Insulin Sensitivity Index | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. When this results in multiple samples at the same time point, only one sample was collected. It was calculated as 10,000/square root ([mean plasma insulin × mean plasma glucose during OGTT or meal challenge] × [fasting plasma glucose × fasting plasma insulin]). The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Up to Day 1 (24 hours) | 
| Part C: Summary of Change From Baseline in Fasted Glucose | Blood samples were collected fasting pre-breakfast and pre-morning dose (PD time 0) on Days -1, 13 and 14 and then at 10, 20, 30, 60, 90, 120, 180 min after eating the standardized breakfast meal tolerance test. For lunch (4 hour post-morning dose) samples were collected just before the meal and after starting each meal: 0.5, 1, 1.5, 2 and 3 hours. For the evening meal (10 hour post-morning dose), BID dosing groups followed the sequence of sampling, food and dosing as for breakfast (PD sample immediately before meal, eat and then dose), then 0.5, 1, 1.5, 2 and 3 hours post-dinner. A sample was also collected 24 hours post-dose. When this results in multiple samples at the same time point, only one sample was collected. Change from Baseline was calculated by subtracting Baseline value minus post-Baseline value. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Baseline (Day 1 pre-dose) and Day -1, 13 and 14. | 
| Part C: Summary of Change From Baseline in Fasted Insulin | Blood samples were collected fasting pre-breakfast and pre-morning dose (PD time 0) on Days -1, 13 and 14 and then at 10, 20, 30, 60, 90, 120, 180 min after eating the standardized breakfast meal tolerance test. For lunch (4 hour post-morning dose) samples were collected just before the meal and after starting each meal: 0.5, 1, 1.5, 2 and 3 hours. For the evening meal (10 hour post-morning dose), BID dosing groups followed the sequence of sampling, food and dosing as for breakfast (PD sample immediately before meal, eat and then dose), then 0.5, 1, 1.5, 2 and 3 hours post-dinner. A sample was also collected 24 hours post-dose. When this results in multiple samples at the same time point, only one sample was collected. Change from Baseline was calculated by subtracting Baseline value minus post-Baseline value. The point estimates and corresponding 95% CI for treatment ratios were calculated for treatment comparisons versus placebo. | Baseline (Day 1 pre-dose) and Day -1, 13 and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Number of Participants With AEs and SAEs | An AE was defined as any untoward MO in a participant temporally associated with the use of a 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. | Up to Week 7 | 
| Part B: Number of Participants With Abnormal Hematology Parameters of PCI | Hematology parameters included platelet count, RBC count, MCV, total neutrophils, WBC absolute, MCH, lymphocytes, MCHC, monocytes, hemoglobin, eosinophils, hematocrit, reticulocytes and basophils. It was assessed on Screening, Day -1, 2 (of each treatment period) and Follow-up (7 to 10 days after final discharge). Only those parameters for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 7 | 
| Part B: Number of Participants With Abnormal Clinical Chemistry Parameters of PCI | Clinical chemistry parameters included BUN, potassium, AST, total and direct bilirubin, creatinine, chloride, ALT, uric acid, glucose fasting, GGT, albumin, sodium, magnesium, phosphorus inorganic, calcium, total CO2, ALP, triglycerides, total cholesterol, LDL cholesterol, free fatty acid (NEFA), HDL cholesterol and total protein. It was assessed on Screening, Day -1, 2 (of each treatment period) and Follow-up (7 to 10 days after final discharge). Only those parameters (Glucose, High) for which at least one value of PCI was reported are summarized. Null data is not presented. | Up to Week 7 | 
| Part B: Number of Participants With Significant ECG Abnormalities | Twelve-lead ECGs was obtained in a supine position at each time point during the study using an ECG machine that automatically measured PR, QRS, QT and QTc intervals (QTcB and QTcF). Participants with abnormal clinically significant ECG findings is presented. It was assessed on Screening, Day 1 at pre-dose, 1, 2, 3, 4, 6, 10, 16, 24 hours and Follow-up (7 -10 days after final discharge). | Up to Week 7 | 
| Part B: Number of Participants With Abnormal Vital Signs of PCI | SBP, DBP and pulse rate measurements were recorded at each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 min. Participants with abnormal clinically significant vital signs findings is presented. It was assessed on Screening, Day -1, 1, 2 (pre-dose, 1, 3, 4, 6, 10, 16 and 24 hours of each treatment period) and Follow-up (7 -10 days after final discharge). | Up to Week 7 | 
| Part B: Summary of Plasma Cmax | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. Blood samples for the determination of PK was collected at on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period. | 
| Part B: Summary of T-max and T-lag | The time at which Cmax was observed was determined directly from the raw concentration-time data. The lag time before observation of drug concentrations in sample matrix determined as the time of the sample preceding the first quantifiable concentration. Blood samples for the determination of PK was collected at on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period | 
| Part B: Summary of AUC0-t and AUC0-24 | The AUC 0-24 and AUC 0-t determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. Blood samples for the determination of PK was collected at on Day 1 of each period: immediately pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours. | Pre-dose (time 0) and at 0.5, 1, 2, 3, 4, 6, 8, 13 and 24 hours on Day 1 of each treatment period | 
| Part B: Summary of Change From Baseline in Fasted Glucose | Blood samples for the determination of glucose were collected at pre-dose on Day 1 of each dosing period and immediately prior to and at 10, 20, 30, 60, 90, 120, 180 min after administration of the 75 grams glucose drink. For lunch and evening meal in Part A, samples were collected just before the meal and at the following times after starting each meal: 0.5, 1, 1.5 (except breakfast in Part B), 2 and 3 hours. When this results in multiple samples at the same time point, only one sample was collected. Change from Baseline was calculated by subtracting Baseline value from post-Baseline value. | Baseline (Day 1 pre-dose) and Day 1 (24 hours) | 
| Part B: Summary of Change From Baseline in Fasted Glucagon, GLP-1, C-peptide, Total GIP, Total PYY and Insulin | Blood samples for the determination of glucose and other PD markers were collected at pre-dose on Day 1 of each dosing period. For breakfast, lunch and evening meal in Part B, samples were collected just after the meal and at the following times after starting each meal: 0.5, 1 and 2 hours. Samples were also collected in Part B at 24 hours post-dose. When this results in multiple samples at the same time point, only one sample was collected. Change from Baseline was calculated by subtracting Baseline value from post-Baseline value. | Baseline (Day 1 pre-dose) and Day 1 (24 hours) | 
| Part C: Summary of Cmax of GSK1292263 and Sitagliptin When Co-administered | The first occurrence of the maximum observed plasma concentration determined directly from the raw concentration-time data. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post-breakfast), 1, 2, 4 (= pre-lunch), 6, 10 (= immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of T-half and Tmax of GSK1292263 and Sitagliptin When Co-administered | The time at which Cmax was observed was determined directly from the raw concentration-time data. The lag time before observation of drug concentrations in sample matrix determined as the time of the sample preceding the first quantifiable concentration. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post-breakfast), 1, 2, 4 (= pre-lunch), 6, 10 (= immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 
| Part C: Summary of AUC0-24, AUC0-t of GSK1292263 and Sitagliptin When Co-administered | The AUC0-10, AUC0-12 and AUC0-24 determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. When GSK1292263 was dosed once daily, blood samples were collected on Days 1, 13 and 14 immediately pre-dose (time 0) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-dose. When GSK1292263 was dosed BID, blood samples were collected on Days 1, 13 and 14, at immediately pre-morning dose, 1,2, 4, 6, 8, 10, 11, 12, 14, 16, 18 and 24 hours post-morning dose. For once daily and BID dosing regimens on Day 7, blood samples were collected at pre-dose (= post- breakfast), 1, 2, 4 (= pre lunch), 6, 10 (= immediately post-dinner) and 12 hours. When planned PK sampling results in multiple samples at the same time point, only one sample was collected. | Days 1, 7, 13 and 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tolerability, Pharmacokinetics, Safety, Pharmacodynamics, Glucose