Study of TAK-559 in Treating Subjects With Type 2 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study was to determine the safety of TAK-559, once daily (QD), in treating subjects receiving a stable dose of insulin to control 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 of TAK-559 in the treatment of patients with type 2 diabetes mellitus who were on a stable dose of insulin.

Official Title
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A Multicenter, Double-Blind, Placebo-Controlled, Randomized Study of the Safety of TAK-559 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 insulin
* Drug: Insulin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Had type 2 diabetes mellitus using American Diabetes Association diagnostic criteria, currently treated with insulin therapy. Required sponsor approval if older than 65 years. Had a Screening glycosylated hemoglobin less than or equal to 8.0%. Had a Screening fasting plasma glucose less than or equal to 200 mg/dL (11.1 mmol/L). Had a Screening low density lipoprotein less than or equal to 160 mg/dL (4.1 mmol/L). Had a Screening thyroid stimulating hormone level less than or equal to 5.5 μU/mL (5.5 μU/L) and greater than or equal to 0.35 μU/mL (0.35 μU/L). Was willing to continue dietary counseling during study and had dietary advice greater than or equal to 2.5 months prior to Screening. Had a Screening ejection fraction greater than or equal to 40% from echocardiogram. Had a Screening blood pressure less than or equal to 140/95 mm Hg. Was willing to perform daily self-monitoring blood glucose tests. A female subject of childbearing potential who was sexually active agreed to use adequate contraception, and was neither pregnant nor lactating from Screening throughout the duration of the study. Was in good health as determined by physician (via medical history and physical examination) other than having type 2 diabetes mellitus. Had clinical laboratory evaluations within normal reference range or deemed not clinically significant by the investigator or sponsor. Started insulin therapy at least 3 months prior to Randomization. Exclusion Criteria: Had a hypersensitivity to peroxisome proliferator-activated receptor -alpha or gamma agonists, thiazolidinediones, or fibrates. Was diagnosed with type 1 diabetes mellitus or hemochromatosis, or had a history of ketoacidosis. Required greater than 2 hypertension medications to achieve adequate blood pressure control. Had a history of coronary angioplasty or bypass graft, or unstable angina pectoris within 1 year of Screening. Had a history of myocardial infarction. Had a history of transient ischemic attack or documented cerebrovascular accident within 6 months of Screening. Abdominal, thoracic, or vascular surgery within 6 months of Screening warranting exclusion (investigator's opinion). Had a screening creatine phosphokinase value greater than 3 times the upper limit of normal. Had persistent unexplained microscopic or macroscopic hematuria or history of bladder cancer. Had a screening triglyceride level greater than 500 mg/dL (5.6 mmol/L). Experienced a change in allowed lipid-lowering medication (dose or drug) within 2 months of Randomization. Experienced a change in blood pressure medication (dose or drug) within 1 month of Randomization. Had systemic corticosteroids within 1 month of Randomization. Had donated or received blood products within 3 months of Randomization. Had a condition known to invalidate glycosylated hemoglobin. Had a history of drug abuse or alcohol abuse within 2 years. Had a significant cardiovascular disease, including New York Heart Association Functional (Cardiac) Classification II, III or IV. Had a Screening B-Type Natriuretic Peptide greater than 100 pg/mL (100 ng/L). Had a history of left ventricular hypertrophy (women greater than 110 g/m2 and men greater than 134 g/m2). Had a clinically significant mitral insufficiency at Screening. Had a clinically significant aortic stenosis at Screening. Had a Screening body mass index greater than 45. Had a history of cancer with no remission within 5 years of Randomization, other than basal cell or stage 1 squamous cell carcinoma of the skin. Had an alanine transaminase or aspartate transaminase level greater than 3 times the upper limit of normal, active liver disease or jaundice at Screening. Had a positive human immunodeficiency virus, hepatitis B surface antigen, or hepatitis B e antigen test at Screening. Was required to take or intended to continue taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfered with the evaluation of the study medication, including: oral antidiabetic agents (including sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, peroxisome proliferator-activated receptor agonists and metformin) fibrates systemic corticosteroids warfarin rifampin nicotinic acid minoxidil hydralazine St. John's Wort Was participating or had participated in an investigational study within the past 30 days. Had a serious disease or condition at Screening or Randomization that could affect life expectancy or made it difficult to manage/follow patient according to protocol.

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 65 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 32 mg QD + Insulin<br> | Drug: TAK-559 and insulin<br>* TAK-559 32 mg, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.<br>|
| Active Comparator: Insulin<br> | Drug: Insulin<br>* TAK-559 placebo-matching, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse events. |  | All visits or at occurrence. | 
| Clinical safety lab tests. |  | Weeks 12, 24, and Final Visit. | 
| 12-lead electrocardiogram. |  | Weeks: 24 and Final Visit. | 
| Urinalysis. |  | Weeks: 12, 24, 36, 48 and Final Visit. | 
| Change from Baseline in Blood pressure and pulse. |  | At all visits. | 
| Change from Baseline in Body weight. |  | At all visits. | 
| Left ventricular mass index by body surface area measured by echocardiogram. |  | Weeks: 24 and Final Visit. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in total daily dose of insulin. |  | At all visits. | 
| Change from Baseline in triglycerides. |  | Weeks: 24 and Final Visit. | 
| Change from Baseline in cholesterol. |  | Weeks 24 and Final Visit | 
| Change from Baseline in total, high-density lipoproteins. |  | Weeks: 24 and Final Visit. | 
| Change from Baseline in low-density lipoproteins. |  | Weeks 24 and Final Visit | 
| Change from Baseline in low-density lipoprotein fractionation. |  | Weeks 24 and Final Visit | 
| Change from Baseline in very low-density lipoprotein. |  | Weeks 24 and Final Visit | 
| Change from Baseline in free fatty acids. |  | Weeks 24 and Final Visit | 
| Change from Baseline in apolipoproteins (AI, B). |  | Weeks 24 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