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

This study has been terminated.
(Hepatic safety signal identified.)
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00762190
First received: September 26, 2008
Last updated: November 8, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Diabetes Mellitus
Drug: TAK-559 and insulin
Drug: Insulin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter, Double-Blind, Placebo-Controlled, Randomized Study of the Safety of TAK-559 in the Treatment of Patients With Type 2 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by Takeda:

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

Secondary Outcome Measures:
  • Change from Baseline in total daily dose of insulin. [ Time Frame: At all visits. ] [ Designated as safety issue: No ]
  • Change from Baseline in triglycerides. [ Time Frame: Weeks: 24 and Final Visit. ] [ Designated as safety issue: No ]
  • Change from Baseline in cholesterol. [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in total, high-density lipoproteins. [ Time Frame: Weeks: 24 and Final Visit. ] [ Designated as safety issue: No ]
  • Change from Baseline in low-density lipoproteins. [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in low-density lipoprotein fractionation. [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in very low-density lipoprotein. [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in free fatty acids. [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in apolipoproteins (AI, B). [ Time Frame: Weeks 24 and Final Visit ] [ Designated as safety issue: No ]

Enrollment: 348
Study Start Date: November 2003
Study Completion Date: December 2004
Primary Completion Date: December 2004 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: TAK-559 32 mg QD + Insulin Drug: TAK-559 and insulin
TAK-559 32 mg, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.
Active Comparator: Insulin Drug: Insulin
TAK-559 placebo-matching, tablets, orally, once daily and insulin stable dose injection for up to 54 weeks.

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   25 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00762190

Sponsors and Collaborators
Takeda
Investigators
Study Director: VP Biological Sciences Takeda
  More Information

No publications provided

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00762190     History of Changes
Other Study ID Numbers: 01-03-TL-559-016, U1111-1128-1034
Study First Received: September 26, 2008
Last Updated: November 8, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda:
Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus, Lipoatrophic
Dyslipidemia
Drug Therapy

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Insulin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 15, 2014