Potential hepatic safety signal

The purpose of this study is to determine the safety and efficacy of TAK-559, once daily (QD), combined with glyburide in treating Type 2 Diabetes.

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.

Inclusion Criteria:

• Must be diagnosed with type 2 diabetes mellitus using American Diabetes Association diagnostic criteria, and on a stable dose of an oral anti-diabetic monotherapy prior to Screening A.
• Has a glycosylated hemoglobin level greater than or equal to 8.0% and less than or equal to 10.0% at Screening B.
• Has a fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L) at Screening B.
• Is taking a stable dose of at least 10 mg of glyburide for at least 10 days prior to Screening B.
• Has a stable or worsening self-monitoring blood glucose level while taking glyburide.
• The patient must have a low-density lipoprotein less than 160 mg/dL (4.1 mmol/L) at Screening A.
• Has a body mass index less than or equal to 45 kg/m2 at Screening A.
• Is willing to be counseled by the investigator or designee to follow an individualized, weight-maintaining diet during the study period.
• Has 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.
• The patient must be able to perform daily self-monitoring blood glucose tests throughout the study.
• Has a normal thyroid-stimulating hormone level of less than 5.5 uIU/mL (5.5 mIU/L) and greater than or equal to 0.35 uIU/mL (0.35 mIU/L) at Screening A.
• Is in good health as determined by a physician (ie, via medical history and physical examination), other than a diagnosis of type 2 diabetes mellitus.
• Has fasting clinical laboratory evaluations within the normal reference range for the testing laboratory, or if not, the results must be deemed not clinically significant by the investigator prior to Randomization.
• Females must be post menopausal, surgically sterile, or using adequate contraception.

Exclusion Criteria:

• Has been diagnosed with type 1 diabetes mellitus, hemochromatosis, or has a history of ketoacidosis.

• Has any condition known to invalidate glycosylated hemoglobin results (eg, hemolytic states, hemoglobinopathies).

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • Insulin
  • Oral anti-diabetics other than TAK-559 (including sulfonylureas other than glyburide, alpha-glucosidase inhibitors, metformin)
  • Systemic corticosteroids
  • Warfarin
  • Rifampin
  • St. John's Wort.
  • Thiazolidinediones
  • Peroxisome proliferator-activated receptor agonists
  • Nicotinic Acid
  • Fibrates

• Has 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 prior to Screening A.

• Has had abdominal, thoracic, or vascular surgery within 6 months prior to Screening A that in the investigator's opinion would warrant exclusion from the study.

• Has a creatine phosphokinase value greater than 3 times the upper limit of normal at Screening A. The creatine phosphokinase value can be retested prior to Randomization if elevated.

• Has had persistent unexplained microscopic or macroscopic hematuria or a history of bladder cancer.

• Has a triglyceride level greater than 500 mg/dL (5.6 mmol/L) at Screening A.

• Has had any alteration in allowed lipid lowering medication (dose or drug) within 2 months of Randomization, if applicable.

• Has donated and/or received any blood or blood products within 3 months prior to Randomization.

• Has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within 2 years prior to Randomization.

• Has a systolic BP greater than 140 mm Hg or a diastolic blood pressure of greater than 95 mm Hg at Screening B.

• Has significant cardiovascular disease including but not limited to, New York Heart Association Functional (Cardiac) Classification III or IV.

• Has a previous history of cancer, other than basal cell or stage 1 squamous cell carcinoma of the skin, that has not been in remission within 5 years prior to Randomization.

• Has an alanine transaminase or aspartate transaminase level greater than 3 times the upper limit of normal, active liver disease, or jaundice at Screening A.

• Has a positive human immunodeficiency virus, hepatitis B surface antigen, or hepatitis B e antigen test at Screening A.

• Has any other serious disease or condition at Screening A or at Randomization that might affect life expectancy or make it difficult to successfully manage and follow the patient according to the protocol.