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

Sponsor

Takeda (Industry)

Overall Status

Completed

CT.gov ID

NCT00762736

Collaborator

(none)

704

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Pioglitazone and azilsartan Drug: Pioglitazone and azilsartan Drug: Pioglitazone Drug: Pioglitazone and azilsartan Drug: Pioglitazone and azilsartan Drug: Pioglitazone	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

704 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, 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

Study Start Date :

Jul 1, 2004

Actual Primary Completion Date :

Oct 1, 2005

Actual Study Completion Date :

Oct 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

Change from Baseline in glycosylated hemoglobin. [Week 24 or Final Visit]

Secondary Outcome Measures

Change from Baseline in glycosylated hemoglobin. [Weeks 12, 16, 20, and 24 or Final Visit]
Change from Baseline in fasting plasma glucose. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in total cholesterol. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in high-density lipoprotein. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in low-density lipoprotein. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in triglycerides. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in body weight. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in systolic and diastolic blood pressure. [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in incidence of edema (peripheral). [Weeks 2, 4, 6, 8. 12, 16, 20, and 24 or Final Visit]
Change from Baseline in microalbuminuria excretion. [Week 24 or Final Visit]
Change from Baseline in high-sensitivity C-reactive protein. [Weeks 12 and 24 or Final Visit]
Change from Baseline in matrix metalloproteinase-9. [Weeks 12 and 24 or Final Visit]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	City	State	Country
1	Birmingham,	Alabama	United States
2	Huntsville	Alabama	United States
3	Sierra Vista	Arizona	United States
4	Sun City	Arizona	United States
5	Tucson	Arizona	United States
6	Burbank	California	United States
7	Escondido	California	United States
8	Irvine	California	United States
9	La Jolla	California	United States
10	National City	California	United States
11	Riverside	California	United States
12	Sacramento	California	United States
13	San Diego	California	United States
14	Spring Valley	California	United States
15	Coral Gables	Florida	United States
16	Deland	Florida	United States
17	Hollywood	Florida	United States
18	Miami	Florida	United States
19	New Port Richey	Florida	United States
20	Opalocka	Florida	United States
21	Pembroke Pines	Florida	United States
22	Sarasota	Florida	United States
23	Vero Beach	Florida	United States
24	Atlanta	Georgia	United States
25	Augusta	Georgia	United States
26	Warner Robins	Georgia	United States
27	Honolulu	Hawaii	United States
28	Lihue	Hawaii	United States
29	Chicago	Illinois	United States
30	Dyersburg	Indiana	United States
31	Overland Park	Kansas	United States
32	Wichita	Kansas	United States
33	New Orleans	Louisiana	United States
34	Shreveport	Louisiana	United States
35	Salisbury	Massachusetts	United States
36	Cadillac	Michigan	United States
37	Detroit	Michigan	United States
38	Livonia	Michigan	United States
39	Kansas City	Missouri	United States
40	St. Louis	Missouri	United States
41	Las Vegas	Nevada	United States
42	North Las Vegas	Nevada	United States
43	Berlin	New Jersey	United States
44	Blackwood	New Jersey	United States
45	Trenton	New Jersey	United States
46	Albany	New York	United States
47	Kingston	New York	United States
48	Charlotte	North Carolina	United States
49	Marion	Ohio	United States
50	Clinton	Oklahoma	United States
51	Oklahoma City	Oklahoma	United States
52	Allentown	Pennsylvania	United States
53	Altoona	Pennsylvania	United States
54	Philadelphia	Pennsylvania	United States
55	Scotland,	Pennsylvania	United States
56	Woonsocket	Rhode Island	United States
57	Greer	South Carolina	United States
58	Arlington	Texas	United States
59	Dallas	Texas	United States
60	Fort Worth	Texas	United States
61	Midland,	Texas	United States
62	North Richard Hills	Texas	United States
63	San Antonio	Texas	United States
64	Renton	Washington	United States
65	Buenos Aires		Argentina
66	Cordoba		Argentina
67	Rosario-Santa Fe		Argentina
68	Santa Fe		Argentina
69	Ushuaia - Tierre del Fuego		Argentina
70	Santiago		Chile
71	Aguascalientes		Mexico
72	Cuernavaca		Mexico
73	Durango		Mexico
74	Guadalajara		Mexico
75	Mexico City		Mexico
76	Pueblo		Mexico
77	Ica		Peru
78	Lima		Peru