A Study of GSK256073 in Subjects With Type 2 Diabetes Mellitus Who Are Being Treated With Metformin

Study Overview
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Brief Summary
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The aim of this combined, two part study is to evaluate the safety and glucose lowering effects of GSK256073 when administered to diabetic subjects for 12 weeks.

Detailed Description
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The study will be conducted at centers in Europe and the United States. The study is being conducted in two parts. Part A (n = 90 subjects) will provide a preliminary evaluation of 12 weeks of treatment. Initiation of part B (n = 210 additional subjects) will be dependent on the results observed in part A. The emerging data from part A will be used to guide selection of the doses in Part B. Up to 8 dose levels of GSK256073 may be included in part B. The emerging exposure response relationships from the part A interim analysis will be used to guide dose selection. Each subject enrolled in the study will undergo screening procedures, a 2 week placebo run-in period, baseline assessments, randomization, a twelve week treatment period, and a 2 week follow-up period. Following completion of the baseline visit and randomization into the study, subjects will return to the clinic for safety and efficacy assessments at Weeks 3, 6, 9, and 12. A subject's total participation in the study will last up to approximately 20 weeks. Subjects will continue their current prescribed regimen of metformin (glucophage) monotherapy and will monitor fasting blood glucose levels daily using a glucometer.

Official Title
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A Multicenter, Two Part, Randomized, Parallel Group, Placebo and Sitagliptin Controlled Study to Evaluate the Safety and Efficacy of GSK256073 Administered Once or Twice Daily for 12 Weeks in Subjects With Type 2 Diabetes Mellitus Who Are Being Treated With Metformin

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: GSK256073 1mg
* Drug: GSK256073 5mg
* Drug: GSK256073 10mg
* Drug: GSK256073 25mg
* Drug: Placebo
* Drug: Sitagliptin 100mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of T2DM as determined by a responsible physician based on a medical evaluation including medical history, physical examination, and laboratory tests, with onset at least 6 months prior to Screening. Subjects may be entered if they have stable hypertension or dyslipidemia on therapy. Subjects with other conditions except as noted in the Exclusion criteria may be included only if the investigator and GSK medical monitor agree that the condition is unlikely to introduce additional risk factors and will not interfere with study procedures HbA1c levels greater than or equal to 7.0 % and less than or equal to 9.5% at Screening On monotherapy with metformin at the time of screening, and at a maximum tolerated dose greater than or equal to 1000 mg for at least 2 months prior to dosing. Fasting plasma glucose level less than 13.3 mmol/L (240 mg/dL) at Screening Male or female between 20 and 70 years of age, inclusive, at the time of signing the informed consent Fasting Triglycerides lower than 4.52 mmol/L (400 mg/dL) A female subject is able to participate is she if of non-child bearing potential Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until 3 days after last dose of the study medication Overweight with BMI greater than or equal to 25 kg/m2 for non-Asian Indians and greater than or equal to 24 kg/m2 for Asian-Indian, and less than 40 kg/m2 The subject is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Subjects in France will be eligible only if they are affiliated to or a beneficiary of a social security category Subjects in other countries must meet all local and/or country-specific requirements for registration and reimbursement, as applicable Exclusion Criteria: Requiring insulin therapy or use of combination oral antidiabetic medications or use of monotherapy other than metformin within the 3 months prior to screening Past or present disease (other than type 2 diabetes mellitus) that in the opinion of the Investigator may affect the outcome of this study A positive pre-study Hepatitis B surface antigen, or positive Hepatitis C result within 3 months of screening Renal impairment as defined by a calculated GFR less than 60 mL/min Any concurrent serious illness (e.g., severe COPD, history of malignancy other than skin cancer within 5 years of initial diagnosis or with evidence of recurrence) that may interfere with a subject completing the study Laboratory values as defined per protocol ECG criteria as defined per protocol Systolic blood pressure greater than 160 mmHg, or diastolic blood pressure greater than 100 mmHg at Screening History of uric acid kidney stone, and being treated with drugs for hyperuricemia including Allopurinol or Probenecid History of peptic ulcer disease (PUD) and/or other gastrointestinal bleeding within the 12 months prior to screening Use of certain blood pressure medications or certain other medications that are renally excreted as defined per protocol History of myopathy or CPK value greater than 3 times upper limit of normal at screening The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives or twice the biological effect (whichever is longer) Exposure to more than four new chemical entities within 12 months prior to the first dosing day Any change in diet, exercise habits or smoking status within six weeks prior to screening. Any subject that cannot refrain from smoking while in the unit must be excluded History of sensitivity to any of the study medications, including sitagliptin or metformin, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation The subject has a positive pre-study drug screen History of regular alcohol consumption within 6 months of the study as defined per protocol Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period Pregnant females as determined by positive serum and/or urine hCG test at screening and prior to dosing Lactating females Subjects who are unwilling or unable to follow the procedures outlined in the protocol Subject is mentally or legally incapacitated

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK256073 1mg bid<br>GSK256073 1mg capsule taken orally twice a day | Drug: GSK256073 1mg<br>* GSK256073 1mg capsule<br>|
| Experimental: GSK256073 2mg qd<br>GSK256073 2 x 1mg capsule taken orally once a day | Drug: GSK256073 1mg<br>* GSK256073 1mg capsule<br>|
| Experimental: GSK256073 5mg bid<br>GSK256073 5mg capsule taken orally twice a day | Drug: GSK256073 5mg<br>* GSK256073 5mg capsule<br>|
| Experimental: GSK256073 10mg qd<br>GSK256073 2 x 5mg capsule taken orally once a day | Drug: GSK256073 5mg<br>* GSK256073 5mg capsule<br>|
| Experimental: GSK256073 10mg bid<br>GSK256073 10mg capsule taken orally twice a day | Drug: GSK256073 10mg<br>* GSK256073 10mg capsule<br>|
| Experimental: GSK256073 20mg qd<br>GSK256073 2x 10mg capsule taken orally once a day | Drug: GSK256073 10mg<br>* GSK256073 10mg capsule<br>|
| Experimental: GSK256073 25mg bid<br>GSK256073 25mg capsule taken orally twice a day | Drug: GSK256073 25mg<br>* GSK256073 25mg capsule<br>|
| Experimental: GSK256073 50mg qd<br>GSK256073 2x 25mg capsule taken orally once a day | Drug: GSK256073 25mg<br>* GSK256073 25mg capsule<br>|
| Placebo Comparator: Placebo<br>Matching placebo capsules taken orally either once a day or twice a day | Drug: Placebo<br>* placebo capsule<br>|
| Active Comparator: Sitagliptin 100mg qd<br>Commercially available Sitagliptin 100mg capsules taken once a day | Drug: Sitagliptin 100mg<br>* Sitagliptin 100mg capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, or is an event of possible drug-induced liver injury. | Up to Week 12 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Mean of triplicate measurements at each time point was considered for the summary. Baseline was defined as pre-dose of Day 1 visit. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. It was assessed on Baseline, Day 1 (12 hours), Day 2 (pre-dose and 12 hours), Week 3, 6 (pre-dose and 12 hours), 9 and 12. | Baseline (pre-dose Day 1) and up to Week 12 | 
| Change From Baseline in Heart Rate | Mean of triplicate measurements at each time point was considered for the summary. Baseline was defined as pre-dose of Day 1 visit. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. It was assessed on Baseline (pre-dose Day 1), Day 1 (12 hours), Day 2, Week 3, 6, 9 and 12. | Baseline (pre-dose Day 1) and up to Week 12 | 
| Number of Participants With Abnormal Electrocardiograms (ECGs) Findings | Single 12-lead ECGs were obtained at each time point during the study using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTc intervals. It was assessed at Baseline (pre-dose Day 1), Day 2, Week 3, Week 6 and 12. Participants with normal, abnormal not clinically significant and abnormal clinically significant ECG were presented. | Up to Week 20 | 
| Number of Participants With Clinical Chemistry Abnormalities of Potential Clinical Importance (PCI) | 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, creatine phosphokinase (CPK) and fasting lipid panel including total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol. It was assessed on Baseline (pre-dose Day 1), Week 3 and 12. Data for parameters with high and low of PCI is provided. | Up to Week 12 | 
| Number of Participants With Hematology Abnormalities of Potential Clinical Importance (PCI) | 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, reticulocyte count, mean corpuscular hemoglobin concentration (MCHC), monocytes, hemoglobin, eosinophils, hematocrit and basophils. It was assessed on Baseline (pre-dose Day 1) and 12. Data for parameters with high and low of PCI is provided. | Up to Week 12 | 
| Number of Participants With Abnormal Urinalysis: Glucose, Protein, Blood and Ketones by Dipstick | Urinalysis parameters included glucose, protein, blood and ketones by dipstick. It was assessed on Baseline (Day -1) and 12. Urine glucose was measured as grams per deciliter (G/dL). | Up to Week 12 | 
| Change From Baseline in Glycated Hemoglobin (HbA1c) at Week 12 | Blood samples for analysis of HbA1c were collected at Baseline (Day -1), Day 41, Week 9 and Week 12. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as Day -1 visit. Statistics is provided for least square mean at Week 12. | Baseline (Day -1) and up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 12 Hour Non-esterified Fatty Acids (NEFA) and Glucose Weighted Mean Concentration Value at Day 2 and at Week 6 | Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as weighted mean value at Day 1 visit. Statistics is provided for least square mean at Week 6. It was assessed on Baseline (Day 1), Day 2 and Week 6. | Baseline (Day 1) and up to Week 6 | 
| GSK256073 AUC and HbA1c at Week 12 Was Evaluated to Establish the Exposure-response Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship | The relationships between drug exposure and HbA1c and relative PD endpoints of interest was planned to be plotted graphically. The data for this outcome measure was not collected. | Up to Week 12 | 
| Change From Baseline in Fasting Plasma Glucose at Week 12 | Mean of triplicate measurements at pre-dose time point were considered for the summary. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean at Week 12. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12. | Baseline (Day 1) and up to Week 12 | 
| Change From Baseline in Fasting Insulin at Week 12 | Mean of triplicate measurements at pre-dose time point were considered for the summary. Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean at Week 12. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12. | Baseline (Day 1) and up to Week 12 | 
| Summary of Homeostatic Model Assessment (HOMA) Index Calculated From Change From Baseline in Fasting Insulin and Fasting Glucose at Week 12 | Mean of triplicate measurements at pre-dose time point was considered for the summary. HOMA was calculated by multiplying insulin concentration with glucose concentration divided by 22.5. Change from Baseline for insulin and glucose was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day 1 pre-dose visit. Statistics is provided for least square mean. It was assessed on Day 1 (pre-dose), 2 (pre-dose), Week 6 (pre-dose) and Week 12. | Baseline (Day 1) and up to Week 12 | 
| Change From Baseline in Fructosamine at Week 6 and Week 12 | Change from Baseline was calculated by subtracting the Baseline values from the corresponding post-treatment values. Baseline was defined as mean of Day -1 visit. Statistics is provided for least square mean. It was assessed on Baseline (Day -1), Day 41 and Week 12. | Baseline (Day -1) and Week 12 | 
| Number of Participants With HbA1c < 7.0% and < 6.5% | Data has been presented for number of participants with their corresponding percentages with HbA1c <7.0% and <6.5%. | Up to Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Dose Ranging, Efficacy