Safety Study of TAK-559 in Treating Subjects With Type 2 Diabetes Mellitus
Primary Purpose
Diabetes Mellitus
Status
Terminated
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
TAK-559
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus focused on measuring Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy.
Eligibility Criteria
Inclusion Criteria:
- Required sponsor approval if older than 80 years.
Had either:
- Successfully completed Protocol 01-03-TL-559-016, or
Participated in either Protocol 01-02-TL-559-013, 01-02-TL-559-014, 01-04-TL-559-028, or 01-04-TL-559-029 and either
- completed the study
- prematurely terminated from the study due to the HbA1c withdrawal criterion after at least 12 weeks of treatment, or
- in the opinion of the investigator, demonstrated a lack of efficacy after at least 16 weeks of treatment and was withdrawn from the study.
- 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.
- Were willing to continue following an individualized weight maintenance diet during the study period.
- Had evidence of insulin secretory capacity, as demonstrated by a fasting C-peptide concentration of greater than or equal to 1.5 ng/mL (0.50 nmol/L) at the prior visit of Protocol 013, 014, 016, 028, or 029.
- Were willing to perform daily self-monitoring blood glucose tests.
- Were in good health at Enrollment, as determined by a physician at the final visit of Protocol 013, 014, 016, 028, or 029 (ie, via medical history and physical examination), other than having type 2 diabetes mellitus and New York Heart Association Classification I or II congestive heart failure.
- Had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis after fasting for at least 8 hours) within the normal reference range for the testing laboratory, unless the results were deemed not clinically significant by the investigator or sponsor, at the prior visit of Protocol 013, 014, 016, 028, or 029.
- Had 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 the prior visit of Protocol 013, 014, 016, 028, or 029.
Exclusion Criteria:
- Had significant cardiovascular disease, including, but not limited to, New York Heart Association Classification III or IV CHF at Enrollment.
- Had a planned surgical or catheter intervention for coronary angioplasty within 12 months after the Enrollment Visit.
- Had a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 95 mm Hg at Enrollment.
- Had symptomatic orthostatic hypotension or systolic blood pressure less than 90 mm Hg at Enrollment.
- Had a history of a clinically significant abnormal electrocardiogram or experienced any cardiovascular event including, but not limited to, myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, or documented cerebrovascular accident during Protocol 013, 014, 016, 028, or 029.
- Had a creatine phosphokinase value above 3 times the upper limit of normal at the prior visit of Protocol 013, 014, 016, 028, or 029.
- Had a triglyceride level greater than 500 mg/dL (5.6 nmol/L) at the prior visit of Protocol 013, 014, 016, 028, or 029.
- Had an alanine aminotransferase or aspartate aminotransferase level above 3 times the upper limit of normal, active liver disease, or jaundice at any time during Protocol 013, 014, 016, 028, or 029.
- Had donated and/or received any blood products within 3 months prior to Enrollment.
- Had used illicit drugs or abused alcohol during participation in Protocol 013, 014, 016, 028, or 029.
- Had experienced another illness occurring at the same time requiring hospitalization during the occurring at the same time 3 weeks before the Enrollment Visit.
- Had experienced any other serious disease or condition during participation in Protocol 013, 014, 016, 028, or 029 that might have affected life expectancy or made it difficult to successfully manage and follow the patient according to the protocol.
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:
- insulin (for patients who participated in Protocol 01-02-TL-559-013, 01-02-TL-559-014, 01-04-TL-559-028, and 01-04-TL-559-029)
- prescription-strength niacin
- fibric acid derivatives
- systemic corticosteroids
- warfarin
- rifampin
- nicotinic acid
- St. John's Wort
- thiazolidinediones
- peroxisome proliferator-activated receptor agonists other than the study drug.
- Had experienced persistent unexplained microscopic or macroscopic hematuria or developed cancer of the bladder while participating in Protocol 013, 014, 016, 028, or 029.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
TAK-559 32 mg QD
Arm Description
Outcomes
Primary Outcome Measures
Change from baseline in clinical laboratory hematology tests.
Change from baseline in clinical laboratory chemistry tests.
Blood pressure measurements.
Pulse measurements.
Body weight.
Physical examinations.
12-lead electrocardiogram.
Adverse event occurrence.
Secondary Outcome Measures
Change from baseline in glycosylated hemoglobin.
Change from baseline in fasting plasma glucose.
Change from baseline in fasting insulin.
Change from baseline in fasting C-peptide.
Change from baseline in triglycerides.
Change from baseline in total cholesterol.
Change from baseline in high-density lipoprotein.
Change from baseline in low-density lipoprotein.
Change from baseline in very-low-density lipoprotein.
Change from baseline in low-density lipoprotein fractionation.
Change from baseline in intermediate-density lipoprotein size.
Change from baseline in large low-density lipoprotein size.
Change from baseline in small low-density lipoprotein size.
Change from baseline in medium-small low-density lipoprotein size.
Change from baseline in very-small low-density lipoprotein size.
Change from baseline in mean low-density lipoprotein size.
Change from baseline in apolipoproteins A1 and B.
Change from baseline in atherosclerosis marker plasminogen activator inhibitor 1.
Change from baseline in atherosclerosis marker fibrinogen.
Change from baseline in inflammation marker Interleukin-6.
Change from baseline in inflammation marker C-reactive protein.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00762112
Brief Title
Safety Study of TAK-559 in Treating Subjects With Type 2 Diabetes Mellitus
Official Title
A Long-Term, Open-Label, Phase 3a Safety Study of Oral TAK-559 (32 mg QD) in the Treatment of Patients With Type 2 Diabetes Mellitus
Study Type
Interventional
2. Study Status
Record Verification Date
November 2012
Overall Recruitment Status
Terminated
Why Stopped
Hepatic safety signal identified.
Study Start Date
November 2003 (undefined)
Primary Completion Date
December 2004 (Actual)
Study Completion Date
December 2004 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Takeda
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study was to determine the long-term safety of TAK-559, once daily (QD), in subjects with Type 2 Diabetes.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus
Keywords
Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy.
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
316 (Actual)
8. Arms, Groups, and Interventions
Arm Title
TAK-559 32 mg QD
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
TAK-559
Intervention Description
TAK-559 32 mg, tablets, orally, once daily for up to 24 months.
Primary Outcome Measure Information:
Title
Change from baseline in clinical laboratory hematology tests.
Time Frame
Week 2 and Months 6, 12, 18, and Final Visit
Title
Change from baseline in clinical laboratory chemistry tests.
Time Frame
Week 2 and Months 6, 12, 18, and Final Visit
Title
Blood pressure measurements.
Time Frame
All visits.
Title
Pulse measurements.
Time Frame
All visits.
Title
Body weight.
Time Frame
All visits.
Title
Physical examinations.
Time Frame
Months 6, 12, 18, and Final Visit
Title
12-lead electrocardiogram.
Time Frame
Months 6, 12, and Final Visit
Title
Adverse event occurrence.
Time Frame
All visits or at occurrence
Secondary Outcome Measure Information:
Title
Change from baseline in glycosylated hemoglobin.
Time Frame
Months 3, 6, 9, 12, 15, 18, 21, and Final Visit
Title
Change from baseline in fasting plasma glucose.
Time Frame
All visits.
Title
Change from baseline in fasting insulin.
Time Frame
Months 3, 6, 9, 12, 15, 18, 21, and Final Visit
Title
Change from baseline in fasting C-peptide.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in triglycerides.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in total cholesterol.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in high-density lipoprotein.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in low-density lipoprotein.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in very-low-density lipoprotein.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in low-density lipoprotein fractionation.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in intermediate-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in large low-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in small low-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in medium-small low-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in very-small low-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in mean low-density lipoprotein size.
Time Frame
Months 6, 12, 18, and Final Visit
Title
Change from baseline in apolipoproteins A1 and B.
Time Frame
Months 12 and Final Visit
Title
Change from baseline in atherosclerosis marker plasminogen activator inhibitor 1.
Time Frame
Months 6, 12, and Final Visit
Title
Change from baseline in atherosclerosis marker fibrinogen.
Time Frame
Months 6, 12, and Final Visit
Title
Change from baseline in inflammation marker Interleukin-6.
Time Frame
Months 6, 12, and Final Visit
Title
Change from baseline in inflammation marker C-reactive protein.
Time Frame
Months 6, 12, and Final Visit
10. Eligibility
Sex
All
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Required sponsor approval if older than 80 years.
Had either:
Successfully completed Protocol 01-03-TL-559-016, or
Participated in either Protocol 01-02-TL-559-013, 01-02-TL-559-014, 01-04-TL-559-028, or 01-04-TL-559-029 and either
completed the study
prematurely terminated from the study due to the HbA1c withdrawal criterion after at least 12 weeks of treatment, or
in the opinion of the investigator, demonstrated a lack of efficacy after at least 16 weeks of treatment and was withdrawn from the study.
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.
Were willing to continue following an individualized weight maintenance diet during the study period.
Had evidence of insulin secretory capacity, as demonstrated by a fasting C-peptide concentration of greater than or equal to 1.5 ng/mL (0.50 nmol/L) at the prior visit of Protocol 013, 014, 016, 028, or 029.
Were willing to perform daily self-monitoring blood glucose tests.
Were in good health at Enrollment, as determined by a physician at the final visit of Protocol 013, 014, 016, 028, or 029 (ie, via medical history and physical examination), other than having type 2 diabetes mellitus and New York Heart Association Classification I or II congestive heart failure.
Had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis after fasting for at least 8 hours) within the normal reference range for the testing laboratory, unless the results were deemed not clinically significant by the investigator or sponsor, at the prior visit of Protocol 013, 014, 016, 028, or 029.
Had 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 the prior visit of Protocol 013, 014, 016, 028, or 029.
Exclusion Criteria:
Had significant cardiovascular disease, including, but not limited to, New York Heart Association Classification III or IV CHF at Enrollment.
Had a planned surgical or catheter intervention for coronary angioplasty within 12 months after the Enrollment Visit.
Had a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 95 mm Hg at Enrollment.
Had symptomatic orthostatic hypotension or systolic blood pressure less than 90 mm Hg at Enrollment.
Had a history of a clinically significant abnormal electrocardiogram or experienced any cardiovascular event including, but not limited to, myocardial infarction, coronary angioplasty or bypass graft, unstable angina pectoris, transient ischemic attacks, or documented cerebrovascular accident during Protocol 013, 014, 016, 028, or 029.
Had a creatine phosphokinase value above 3 times the upper limit of normal at the prior visit of Protocol 013, 014, 016, 028, or 029.
Had a triglyceride level greater than 500 mg/dL (5.6 nmol/L) at the prior visit of Protocol 013, 014, 016, 028, or 029.
Had an alanine aminotransferase or aspartate aminotransferase level above 3 times the upper limit of normal, active liver disease, or jaundice at any time during Protocol 013, 014, 016, 028, or 029.
Had donated and/or received any blood products within 3 months prior to Enrollment.
Had used illicit drugs or abused alcohol during participation in Protocol 013, 014, 016, 028, or 029.
Had experienced another illness occurring at the same time requiring hospitalization during the occurring at the same time 3 weeks before the Enrollment Visit.
Had experienced any other serious disease or condition during participation in Protocol 013, 014, 016, 028, or 029 that might have affected life expectancy or made it difficult to successfully manage and follow the patient according to the protocol.
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:
insulin (for patients who participated in Protocol 01-02-TL-559-013, 01-02-TL-559-014, 01-04-TL-559-028, and 01-04-TL-559-029)
prescription-strength niacin
fibric acid derivatives
systemic corticosteroids
warfarin
rifampin
nicotinic acid
St. John's Wort
thiazolidinediones
peroxisome proliferator-activated receptor agonists other than the study drug.
Had experienced persistent unexplained microscopic or macroscopic hematuria or developed cancer of the bladder while participating in Protocol 013, 014, 016, 028, or 029.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
VP Biological Sciences
Organizational Affiliation
Takeda
Official's Role
Study Director
12. IPD Sharing Statement
Learn more about this trial
Safety Study of TAK-559 in Treating Subjects With Type 2 Diabetes Mellitus
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