Efficacy and Safety of Pioglitazone and Azilsartan in Treating Subjects With Type 2 Diabetes Mellitus

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT00762736
First received: September 26, 2008
Last updated: February 27, 2012
Last verified: February 2012
  Purpose

The purpose of this study is to determine the efficacy of pioglitazone, once daily (QD), combined with azilsartan in the treatment of subjects with Type 2 Diabetes Mellitus.


Condition Intervention Phase
Diabetes Mellitus
Drug: Pioglitazone and azilsartan
Drug: Pioglitazone
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II, Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study of the Efficacy, Safety, and Tolerability of Pioglitazone HCl (ACTOS™) in Combination With TAK-536 in Subjects With Type II Diabetes

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Change from Baseline in glycosylated hemoglobin. [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change from Baseline in glycosylated hemoglobin. [ Time Frame: Weeks 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in fasting plasma glucose. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in total cholesterol. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in high-density lipoprotein. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in low-density lipoprotein. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in triglycerides. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in body weight. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in systolic and diastolic blood pressure. [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in incidence of edema (peripheral). [ Time Frame: Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in microalbuminuria excretion. [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in high-sensitivity C-reactive protein. [ Time Frame: Weeks 12 and 24 or Final Visit ] [ Designated as safety issue: No ]
  • Change from Baseline in matrix metalloproteinase-9. [ Time Frame: Weeks 12 and 24 or Final Visit ] [ Designated as safety issue: No ]

Enrollment: 704
Study Start Date: July 2004
Study Completion Date: October 2005
Primary Completion Date: October 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Pioglitazone 15 mg QD + Azilsartan 5 mg QD Drug: Pioglitazone and azilsartan
Pioglitazone 15 mg, tablets, orally, once daily and azilsartan 5 mg, tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
  • TAK-536
Experimental: Pioglitazone 15 mg QD + Azilsartan 40 mg QD Drug: Pioglitazone and azilsartan
Pioglitazone 15 mg, tablets, orally, once daily and azilsartan 40 mg, tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
  • TAK-536
Active Comparator: Pioglitazone 15 mg QD Drug: Pioglitazone
Pioglitazone 15 mg, tablets, orally, once daily and azilsartan placebo-matching tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
Experimental: Pioglitazone 45 mg QD + Azilsartan 5 mg QD Drug: Pioglitazone and azilsartan
Pioglitazone 45 mg, tablets, orally, once daily and azilsartan 5 mg, tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
  • TAK-536
Experimental: Pioglitazone 45 mg QD + Azilsartan 40 mg QD Drug: Pioglitazone and azilsartan
Pioglitazone 45 mg, tablets, orally, once daily and azilsartan 40 mg, tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833
  • TAK-536
Active Comparator: Pioglitazone 45 mg QD Drug: Pioglitazone
Pioglitazone 45 mg, tablets, orally, once daily and azilsartan placebo-matching tablets, orally, once daily for up to 24 weeks.
Other Names:
  • ACTOS®
  • AD4833

Detailed Description:

Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes has a genetic predisposition, but lifestyle, body constitution and age play important roles in determining its time of onset and severity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral-tissue cells to circulating insulin (i.e., insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (i.e., insulin deficiency due to beta cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 15.7 million people have diabetes, with type 2 diabetes occurring in approximately 90-95% of cases.

Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. The oral therapeutic agents used in the treatment of type 2 diabetes can be separated into the following four categories based on their mechanisms of action: insulin secretagogues, inhibitors of hepatic glucose output, inhibitors of complex carbohydrate breakdown in the intestine and insulin sensitizers.

Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis) with no direct impact on insulin secretion. Thus thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors -gamma receptors is in adipose tissue. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd.

Research suggests that Angiotensin II receptor blockers are involved in endothelial and cardiovascular function, and in insulin sensitization and obesity. TAK-536 (azilsartan) is an angiotensin II receptor antagonist with affinity for and selective antagonistic activity at the angiotensin II type 1 receptor.

This study was designed to evaluate the efficacy, safety, and tolerability of pioglitazone in combination with azilsartan in subjects with type 2 diabetes.

Study participation is anticipated to be approximately 6 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Had type 2 diabetes, with a hemoglobin value of greater than or equal to 8.0% or less than 10.0% at Screening.
  • Females of childbearing potential who were sexually active agreed to use adequate contraception, and were neither pregnant nor lactating from Screening throughout the duration of the study.
  • Received antihypertensive therapy and must have been on a stable dose for a minimum of 8 weeks prior to Screening.
  • Had clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory unless the results were deemed not clinically significant for inclusion into this study by the investigator or sponsor.
  • Had been on stable diet and exercise program and oral anti-glycemic therapy including sulfonylurea or metformin for 8 weeks prior to Screening.

Exclusion Criteria:

  • Had a hemoglobin value less than 8.0% or greater than 10.0% at Screening.
  • Was taking an angiotensin II receptor blocker.
  • Had uncontrolled hypertension defined as systolic blood pressure greater than 160 mm Hg and diastolic blood pressure greater than 100 mm Hg. - Had a systolic blood pressure less than or equal to 110 mm Hg and/or diastolic blood pressure less than or equal to 60 mm Hg.
  • Was taking or was expected to take the following medications:

    • antidiabetic agents (other than sulfonylurea or metformin)
    • tricyclic antidepressants
    • monoamine oxidase inhibitors
    • phenothiazines
    • diet medications
    • amphetamines or their derivatives
    • lithium
    • common cold medications with chronic use
    • nonsteroidal anti-inflammatory drugs with chronic use (including aspirin greater than 325 mg/day or cyclooxygenase 2 inhibitors).
  • Had unstable angina or heart failure of any etiology with functional class New York Heart Association III or IV.
  • Had a history of myocardial infarction.
  • Had clinically significant cardiac conduction defects (eg, second or third degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation or flutter).
  • Had secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
  • Had a history of collagen vascular disorder (eg, systemic lupus erythematosus, scleroderma) within the last 5 years.
  • Had a body mass index greater than 39 kg/m2.
  • Had significant, moderate-to-severe renal dysfunction (creatinine greater than 2.4 mg/dL). If receiving metformin, a creatinine greater than 1.5 mg/dL for male subjects or greater than 1.4 mg/dL for female subjects led to exclusion.
  • Had a history of drug abuse or a history of alcohol abuse within the past 2 years.
  • Had a previous history of cancer, other than basal cell carcinoma, that had not been in remission for at least 5 years prior to the first dose of study drug.
  • Had type 2 diabetes with clinically important retinopathy or peripheral or autonomic neuropathy.
  • Had an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
  • Was participating in another investigational study or had participated in an investigational study within 30 days prior to randomization.
  • Had any other serious disease or condition at Screening (or randomization) that might have compromised subject safety, affected life expectancy, or made it difficult to successfully manage and follow the subject according to the protocol.
  • Was hypersensitive to angiotensin II receptor blockers.
  • Was hypersensitive to thiazolidinediones.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00762736

  Show 78 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: VP Clinical Science Strategy Takeda
  More Information

Additional Information:
No publications provided

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00762736     History of Changes
Other Study ID Numbers: 01-04-TL-OPI-525, U1111-1115-8992
Study First Received: September 26, 2008
Last Updated: February 27, 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
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 24, 2014