Subjects with type 2 diabetes mellitus who are being treated with metformin. MedDRA version: 14.1 Level: PT Classification code 10067585 Term: Type 2 diabetes mellitus System Organ Class: 10027433 - Metabolism and nutrition disorders
Conditions
Interventions
Product Name: GSK256073
Product Code: GSK256073
Pharmaceutical Form: Capsule, hard
Current Sponsor code: GSK256073
Other descriptive name: GSK256073F
Concentration unit: mg milligram(s)
Concentration
Sponsors
GlaxoSmithKline R&D Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: A subject will be eligible for inclusion in this study only if all of the following criteria apply: 1. 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. 2. HbA1c levels = 7.0 % and = 9.5%; at Screening. 3. On monotherapy with metformin at the time of screening, and at a total daily dose greater than or equal to 1000 mg for at least 2 months prior to dosing. 4. Fasting plasma glucose level 40 MlU/ml and estradiol =65 years) yes F.1.3.1 Number of subjects for this age range 70
Exclusion criteria
Exclusion criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: 1. Requiring insulin therapy or use of combination oral antidiabetic medications or use of monotherapy other than metformin within the 3 months prior to screening. 2. Past or present disease (other than type 2 diabetes mellitus) that in the opinion of the Investigator may affect the outcome of this study. These diseases include the following but are not limited to, cardiovascular disease, malignancy, hepatic disease, renal disease, haematological disease, neurological disease, gastrointestinal disease and endocrine disease. 3. A positive pre-study Hepatitis B surface antigen, or positive Hepatitis C result within 3 months of screening. 4. Renal impairment as defined by a calculated GFR 2xULN is acceptable if bilirubin is fractionated and direct bilirubin 100 bpm PR Interval 220 ms QRS duration 120 ms QTC Interval (Bazett’s, or Frederica’s if it is automatically calculated)* > 450 ms (>480 msec in subjects with partial Right Bundle Branch Block) 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. * Note that if ECG abnormalities are identified, the average of 3 values taken approximately 5 minutes apart should be used to determine eligibility. 8. Systolic blood pressure greater than 160 mmHg, or diastolic blood pressure greater than 100 mmHg at Screening. 9. History of uric acid kidney stone, and being treated with drugs for hyperuricemia including Allopurinol or Probenicid. 10. History of peptic ulcer disease (PUD) and/or other gastrointestinal bleeding within the 12 months prior to screening. 11. Use of the following blood pressure medications or other medications that are renally excreted via OAT is prohibited: Enalapril (at any dose), Losartan (at any dose), Captopril (at any dose) and ongoing use of niacin or niacin containing medication. Please refer to Section 9.2 of protocol or consult GSK medical monitor. 12. History of myopathy or CPK value > 3 x ULN at screening. 13. 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). 14. Exposure to more than four new chemical entities within 12 months prior to the first dosing day. 15. 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. 16. 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. 17. T
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the safety and efficacy of 12 weeks of daily dosing with GSK256073 in subjects with T2DM who are on metformin monotherapy. In Part B of the study ,an open label active commercial comparator arm, sitagliptin 100mg tablets will be used and will be locally sourced by the clinical study centers. The decision to initiate Part B will be made by the GSK clinical study team based on an evaluation of data from part A. Futility criteria will be applied to allow the study to be terminated, if the part A interim analyses show that there is little chance that the desired week 12 HbA1c effects could be demonstrated in the final study analysis (pooled part A and part B data). The predefined futility criteria is detailed in section 6.3.2. in the protocol. If safety issues are identified across all doses such that none of the doses studies in Part A are deemed safe for progression, the study will stopped.;Secondary Objective: •To characterize the exposure-response PK/PD relationship for change from baseline in week 12 HbA1c. • To assess the effects of 12 weeks daily dosing with GSK256073 on fasting plasma glucose • To assess the effects of 12 weeks daily dosing with GSK 256073 on insulin sensitivity relative to placebo. • To assess the effects of 6 weeks and 12 weeks daily dosing with GSK256073 on fructosamine • To determine number of subjects achieving HbA1c treatment targets for diabetes management. • To characterize the exposure response PK/PD relationship with selected secondary endpoints, if feasible. Secondary (Part A) • To evaluate the sustainability of effects, and to examine the correlation between week 6 NEFA inhibition and glucose lowering. Exploratory • To assess changes from baseline in body weight and additional metabolic biomarkers, including plasma lipids.;Primary end point(s): • Safety and tolerability parameters include: adverse events, clinical laboratory tests, electrocardiograms (ECGs), and vital signs. • The primary efficacy endp | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary • GSK256073 AUC and HbA1c at week 12 will be evaluated to establish the exposure-response (PK/PD) relationship. • Change from baseline in fasting plasma glucose at week 12. • Change from baseline in fasting insulin and fasting glucose at week 12. These values will be used to calculate the Homeostatic Model Assessment (HOMA) index. • Change from baseline in fructosamine at week 6 and week 12. • Percentage of subjects with HbA1c < 7.0% and < 6.5%. • Dose/exposure response relationship using PK/PD modeling for selected secondary endpoints. Secondary (Part A) • Change from baseline in 12 hour NEFA and glucose weighted mean AUC on day 2 and at week 6. Exploratory • Change from baseline in Total cholesterol, HDL, LDL and triglycerides at week 12. • Change from baseline in body weight at week 12. • Change from baseline in uric acid at week 12. • Change from baseline in microalbuminuria at week 12. • Metabolic markers to be analyzed at study completion after review of primary endpoint (examples include but are not limited to: Leptin, Adiponectin, IGF-1, IL-6, CRP, Homocysteine);Timepoint(s) of evaluation of this end point: 12 weeks | — |
Countries
Spain, United Kingdom, United States
Contacts
Public ContactClinical Trials Helpdesk
GlaxoSmithKline
Outcome results
None listed