Efficacy and Safety of TAK-559 Combined With Glyburide in Treating Subjects With Type 2 Diabetes Mellitus. (ORIGAMI)
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|ClinicalTrials.gov Identifier: NCT00759720|
Recruitment Status : Terminated (Potential hepatic safety signal)
First Posted : September 25, 2008
Last Update Posted : February 2, 2012
|Condition or disease||Intervention/treatment||Phase|
|Diabetes Mellitus||Drug: TAK-559 and glyburide Drug: Glyburide||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||447 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|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|
|Study Start Date :||November 2003|
|Actual Primary Completion Date :||December 2004|
|Actual Study Completion Date :||December 2004|
|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.
- 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 ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00759720
|Study Director:||Sr VP Clinical Research||Takeda|