Safety and Efficacy of TAK-559 in Combination With Metformin in Patients With Type 2 Diabetes Mellitus.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of TAK-559, once daily (QD), taken in combination with metformin in treating subjects with type 2 diabetes mellitus

Detailed Description
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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 safety and glycemic control of TAK-559 in patients with type 2 diabetes mellitus taking metformin for whom monotherapy with an oral anti-diabetic had been insufficient.

Official Title
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A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel Study of the Safety and Efficacy of a Combination of TAK-559 and Metformin Compared to Placebo and Metformin in the Treatment of Patients With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: TAK-559 and metformin
* Drug: TAK-559 and metformin
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with type 2 diabetes mellitus, and on a stable dose of an oral antidiabetic monotherapy before Screening A. Female patients of childbearing potential who were sexually active agreed to use adequate contraception, and could neither pregnant nor lactating from Screening throughout the duration of the study. Had a glycosylated hemoglobin level greater than or equal to 8.0% and less than or equal to 10.0% at Screening B. Had a fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L) at Screening B. Taking a stable dose of at least 1000 mg of metformin for at least 30 days before Screening B. Had a stable or worsening self-monitoring blood glucose level while taking metformin. Had a low-density lipoprotein less than 160 mg/dL (4.1 mmol/L) at Screening A. Had a body mass index was less than or equal to 45 kg/m2 at Screening A. Was willing to be counseled by the investigator or designee to follow an individualized, weight-maintaining diet during the study period. Had evidence of insulin secretory capacity as demonstrated by a C-peptide concentration of greater than or equal to 1.5 ng/mL (0.50 nmol/L) at Screening A, and if necessary, after a repeat at Screening B. Was able to perform daily self-monitoring blood glucose tests throughout the study. Had a normal thyroid-stimulating hormone level of less than 5.5 μIU/mL (5.5 mIU/L) and greater than or equal to 0.35 μIU/mL (0.35 mIU/L) at Screening A. Was in good health as determined by a physician (ie, via medical history and physical examination), other than a diagnosis of type 2 diabetes mellitus. Had fasting clinical laboratory results within the normal ranges for the testing laboratory, or if not, the results were deemed not clinically significant by the investigator before Randomization. Exclusion Criteria: Diagnosed with type 1 diabetes mellitus, hemochromatosis, or had a history of ketoacidosis. Had any condition known to invalidate glycosylated hemoglobin results (eg, hemolytic states or hemoglobinopathies). Took any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including: Insulin Oral antidiabetics including sulfonylureas and alpha-glucosidase inhibitors Systemic corticosteroids Warfarin Rifampin St. John's Wort. Thiazolidinediones Peroxisome proliferator-activated receptor agonists Nicotinic Acid Fibrates Had a history of myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, clinically significant abnormal electrocardiogram, or documented cerebrovascular accident within 6 months before Screening A. Had abdominal, thoracic, or vascular surgery within 6 months before Screening A that in the investigator's opinion warranted exclusion from the study. Had a creatine phosphokinase value greater than 3 times the upper limit of normal at Screening A. Had persistent unexplained microscopic or macroscopic hematuria or a history of bladder cancer. Had a triglyceride level greater than 500 mg/dL (5.6 mmol/L) at Screening A. Received any alteration in allowed lipid lowering medication (dose or drug) within 2 months of Randomization, if applicable. The patient remained on a stable dose throughout the study. If deemed necessary, the dose could have been lowered with prior approval from the Sponsor. Donated and/or received any blood or blood products within 3 months before Randomization. Had a history of drug abuse or a history of alcohol abuse within 2 years before Randomization Had a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure of greater than 95 mm Hg at Screening B. Had significant cardiovascular disease including but not limited to, New York Heart Association Functional (Cardiac) Classification III or IV. Had a history of cancer other than basal cell or stage 1 squamous cell carcinoma of the skin that had not been in remission within 5 years before Randomization. Had an alanine aminotransferase or aspartate aminotransferase level greater than 3 times the upper limit of normal, active liver disease, or jaundice at Screening A. Had a positive anti-hepatitis B surface antigen, or anti-hepatitis B e antigen test results at Screening A. Was currently taking another investigational study medication or had taken an investigational study medication within 30 days before Screening A. Had any other serious disease or condition at Screening A or at Randomization that might have affected life expectancy or made it difficult to successfully manage and follow the patient according to the protocol.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-559 16 mg QD + Metformin QD<br> | Drug: TAK-559 and metformin<br>* TAK-559 16 mg, tablets, orally, once daily and metformin stable dose orally, once daily for up to 26 weeks.<br>|
| Experimental: TAK-559 32 mg QD + Metformin QD<br> | Drug: TAK-559 and metformin<br>* TAK-559 32 mg, tablets, orally, once daily and metformin stable dose, orally, once daily for up to 26 weeks.<br>|
| Active Comparator: Metformin QD<br> | Drug: Metformin<br>* TAK-559 placebo-matching tablets, orally, once daily and metformin stable dose, orally, once daily for up to 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in glycosylated hemoglobin. |  | Final Visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in glycosylated hemoglobin. |  | Weeks 2, 4, 8, 12, 16 and 20 | 
| Change from baseline in fasting plasma glucose. |  | Weeks 2, 4, 8, 12, 16, 20 and Final Visit | 
| Change from baseline in serum insulin. |  | Weeks 4, 12, 16, 20 and Final Visit. | 
| Change from baseline in C-peptide. |  | Weeks 4, 12, 16, 20 and Final Visit. | 
| Change from baseline in triglycerides. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in total cholesterol. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in high-density lipoprotein. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in low-density lipoprotein. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in very-low-density lipoprotein. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in apolipoproteins A1 and B 100. |  | Final Visit | 
| Change from baseline in free fatty acids. |  | Weeks 12, 16, 20 and Final Visit. | 
| Change from baseline in thrombosis marker plasminogen activator inhibitor-1 |  | Weeks 4, 12, 16, 20 and Final Visit | 
| Change from baseline in thrombosis marker fibrinogen. |  | Weeks 4, 12, 16, 20 and Final Visit | 
| Change from baseline in inflammation marker Interleukin-6. |  | Weeks 4, 12, 16, 20 and Final Visit | 
| Change from baseline in inflammation marker C-reactive protein. |  | Weeks 4, 12, 16, 20 and Final Visit | 
| Change from baseline in urinary albumin to creatinine ratio. |  | Weeks 12, 16, 20 and Final Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy