Official Title: “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”

The purpose of this study is to evaluate the safety and efficacy of TAK-559 taken in combination with metformin in treating subjects with type 2 diabetes mellitus

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2004

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.

Intervention(s) in this Clinical Trial

• Drug: TAK-559 and metformin
  • TAK-559 16 mg, tablets, orally, once daily and metformin stable dose orally, once daily for up to 26 weeks.
• Drug: TAK-559 and metformin
  • TAK-559 32 mg, tablets, orally, once daily and metformin stable dose, orally, once daily for up to 26 weeks.
• Drug: Metformin
  • TAK-559 placebo-matching tablets, orally, once daily and metformin stable dose, orally, once daily for up to 26 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Experimental: 2
• Placebo Comparator: 3

Primary Measures

• Change from baseline in glycosylated hemoglobin.
  • Time Frame: Final Visit.
    Safety Issue?: No

Secondary Measures

• Change from baseline in glycosylated hemoglobin.
  • Time Frame: Weeks 2, 4, 8, 12, 16 and 20
    Safety Issue?: No
• Change from baseline in fasting plasma glucose.
  • Time Frame: Weeks 2, 4, 8, 12, 16, 20 and Final Visit
    Safety Issue?: No
• Change from baseline in serum insulin.
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in C-peptide.
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in triglycerides.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in total cholesterol.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in high-density lipoprotein.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in low-density lipoprotein.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in very-low-density lipoprotein.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in apolipoproteins A1 and B 100.
  • Time Frame: Final Visit
    Safety Issue?: No
• Change from baseline in free fatty acids.
  • Time Frame: Weeks 12, 16, 20 and Final Visit.
    Safety Issue?: No
• Change from baseline in thrombosis marker plasminogen activator inhibitor-1
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit
    Safety Issue?: No
• Change from baseline in thrombosis marker fibrinogen.
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit
    Safety Issue?: No
• Change from baseline in inflammation marker Interleukin-6.
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit
    Safety Issue?: No
• Change from baseline in inflammation marker C-reactive protein.
  • Time Frame: Weeks 4, 12, 16, 20 and Final Visit
    Safety Issue?: No
• Change from baseline in urinary albumin to creatinine ratio.
  • Time Frame: Weeks 12, 16, 20 and Final Visit
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 25 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

VP Biological Sciences Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00762957

Study ID Number: 01-04-TL-559-029

ClinicalTrials.gov Identifier: NCT00762957

Health Authority: United States: Food and Drug Administration