Efficacy and Safety of TAK-559 Combined With Glyburide in Treating Subjects With Type 2 Diabetes Mellitus. (ORIGAMI)
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel Study of the Safety and Efficacy of a Combination of TAK-559 and Glyburide Compared to Placebo and Glyburide in the Treatment of Patients With Type 2 Diabetes Mellitus|
- Change from Baseline in Glycosylated hemoglobin level. [ Time Frame: Final Visit ]
- Change from baseline in Glycosylated hemoglobin level. [ Time Frame: Weeks: 4, 8, 12, 16 and 20. ]
- Change from baseline in Fasting plasma glucose. [ Time Frame: At all Visits. ]
- Change from Baseline in Serum insulin. [ Time Frame: Weeks: 4, 12, 16, 20 and Final Visit. ]
- Change from Baseline in C-peptide. [ Time Frame: Weeks: 4, 12, 16, 20 and Final Visit. ]
- Change from Baseline in Lipids (triglyceride, total cholesterol, high-density lipoprotein, low-density lipoprotein and very low-density lipoproteins) [ Time Frame: Weeks: 12, 16, 20 and Final Visit. ]
- Change from Baseline in Apolipoproteins [A1 and B]). [ Time Frame: Final Visit ]
- Change from Baseline in Free fatty acids. [ Time Frame: Weeks: 12, 16, 20 and Final Visit. ]
- Markers of thrombosis (plasminogen activator inhibitor-1 and fibrinogen). [ Time Frame: Weeks: 4, 12, 16, 20 and Final Visit. ]
- Markers of inflammation (interleukin-6 and C-reactive protein). [ Time Frame: Weeks: 4, 12, 16, 20 and Final Visit. ]
- Urinary albumin/creatinine ratio. [ Time Frame: Weeks: 4, 12, 16, 20 and Final Visit. ]
- Low-density lipoprotein fractionation [L-DL particles (total), intermediate-density lipoprotein, large L-DL, small L-DL (total), medium-small L-DL, very-small L-DL, mean L-DL size]. [ Time Frame: Weeks 12, 16, 20, and Final Visit ]
|Study Start Date:||November 2003|
|Study Completion Date:||December 2004|
|Primary Completion Date:||December 2004 (Final data collection date for primary outcome measure)|
|Experimental: TAK-559 16 mg QD + Glyburide QD||
Drug: TAK-559 and glyburide
TAK-559 16 mg, tablets, orally, once daily and glyburide stable dose orally, once daily for up to 26 weeks.
|Experimental: TAK-559 32 mg QD + Glyburide QD||
Drug: TAK-559 and glyburide
TAK-559 32 mg, tablets, orally, once daily and glyburide stable dose, orally, once daily for up to 26 weeks.
|Active Comparator: Glyburide QD||
TAK-559 placebo-matching tablets, orally, once daily and glyburide stable dose, orally, once daily for up to 26 weeks.
Insulin is a primary regulator of blood glucose concentrations. A subnormal response to circulating insulin levels at target tissues leads to a decrease in insulin-mediated glucose uptake. Insulin resistance is associated with normal to high insulin levels and is often accompanied by dyslipidemia, a disruption in lipid metabolism resulting in increased triglycerides and low-density lipoprotein levels as well as decreased high-density lipoprotein levels in patients with type 2 diabetes mellitus. In the early stages of insulin resistance, a compensatory mechanism of increased insulin secretion by the pancreas maintains normal to near-normal glucose levels. Once the pancreas fails to maintain the increased insulin output, overt type 2 diabetes mellitus occurs.
Insulin also plays an important role in the metabolism of fat and proteins and exerts its influence at the peroxisome proliferator-activated receptor level. Peroxisome proliferator-activated receptor -alpha receptors are expressed predominantly in skeletal muscle, adipose tissue, heart, liver, kidney, gut, macrophages, and vascular tissue, and play a key role in energy storage, glucose homeostasis, and vascular biology. Thus, as insulin activates peroxisome proliferator-activated receptor-alpha receptors, this results in the cellular uptake of glucose. Peroxisome proliferator-activated receptor receptors are ligand-activated transcription elements that regulate gene expression necessary for metabolism. For this reason, peroxisome proliferator-activated receptors play a pivotal role in glucose homeostasis, adipocyte differentiation, and lipid storage. The genes predominantly targeted by transcription activity of activated peroxisome proliferator-activated receptor-alpha receptors are those that mediate fatty acid uptake, fatty acid oxidation, and lipoprotein metabolism. As such, peroxisome proliferator-activated receptor-alpha agonists have their greatest effect on lipid metabolism and vascular biology.
TAK-559 is a novel oxyiminoalkanoic acid under investigation for use as an oral agent in the treatment of patients with type 2 diabetes mellitus. TAK-559 has partial peroxisome proliferator-activated receptor-alpha agonist activity, potent peroxisome proliferator-activated receptor-alpha activity, and modest peroxisome proliferator-activated receptor-gamma activity at high concentrations in nonclinical models.
This study was designed to evaluate the glycemic control and safety of TAK-559 in patients with type 2 diabetes mellitus taking glyburide for whom monotherapy with an oral anti-diabetics had been insufficient.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00759720
|Study Director:||Sr VP Clinical Research||Takeda|