Efficacy of Alogliptin and Pioglitazone in Subjects With Type 2 Diabetes Mellitus

NCT ID: NCT00432276

Last Updated: 2013-04-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 803 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2009-06-30

Brief Summary

The purpose of the study is to compare the effect of adding alogliptin, once daily (QD), to the ongoing treatment regimen of pioglitazone HCl and metformin in patients with inadequate glycemic control.

Detailed Description

Despite the introduction of new classes of medications for glycemic control, just over half of adults with type 2 diabetes mellitus (T2DM) achieve a glycosylated hemoglobin level less than 7.0%, the American Diabetes Association recommended glycosylated hemoglobin goal. The rising incidence of type 2 diabetes mellitus along with limitations of the currently available treatments suggest the need for new therapies for glycemic control along with the increased requirement for combination therapy in type 2 diabetes mellitus.

Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal through an incompletely understood mechanism but one associated with binding of the drug to nuclear receptors known as peroxisome proliferator-activated receptors-gamma. Peroxisome proliferator-activated receptors-gamma 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. 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. Pioglitazone HCl (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan). Pioglitazone depends on the presence of insulin for its mechanism of action. Worldwide clinical investigation has shown that, as an adjunct to diet and exercise, pioglitazone improves glycemic control when used as monotherapy, and in combination with commonly used antidiabetic medications (ie, sulfonylureas, metformin, or insulin).

SYR-322 (alogliptin) is a selective, orally available inhibitor of dipeptidyl peptidase IV currently in development by Takeda Global Research & Development Center, Inc. as a treatment for type 2 diabetes mellitus. Dipeptidyl peptidase IV is the primary enzyme involved in the in vivo degradation of at least 2 peptide hormones released in response to nutrient ingestion, namely glucagon-like peptide-1 and glucose-dependent insulinotropic peptide. Both peptides exert important effects on islet β-cells to stimulate glucose-dependent insulin secretion and regulate β-cell proliferation and cytoprotection. Glucagon-like peptide-1 also inhibits gastric emptying, glucagon secretion, and food intake. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes.

Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity) and the absence of overlapping safety risks, the introduction of this combination therapy in patients with T2DM could potentially show enhanced glycemic control and allow patients to reach and maintain their HbA1c goal more effectively.

This study is designed to determine if the addition of alogliptin to a combination of pioglitazone with metformin can be effective at achieving glycemic control without increasing safety risks versus the titration of pioglitazone to 45 mg with metformin in patients with type 2 diabetes mellitus who are experiencing inadequate glycemic control on a current regimen of metformin.

Conditions

Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Alogliptin 25 mg + Pioglitazone 30 mg add-on to Metformin

Alogliptin 25 mg, tablets, orally, once daily; pioglitazone 30 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Metformin

Intervention Type: DRUG

Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.

Placebo

Intervention Type: DRUG

Matching placebo tablets.

Pioglitazone 45 mg add-on to Metformin

Alogliptin placebo-matching tablets, orally, once daily; pioglitazone 45 mg, tablets, orally, once daily; and the maximum tolerated dose of metformin, tablets, orally, for up to 52 weeks.

Group Type: ACTIVE_COMPARATOR

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Metformin

Intervention Type: DRUG

Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.

Placebo

Intervention Type: DRUG

Matching placebo tablets.

Interventions

Alogliptin

Alogliptin tablets.

Intervention Type: DRUG

Pioglitazone

Pioglitazone tablets.

Intervention Type: DRUG

Metformin

Metformin HCl tablets (immediate-release, commercially available formulation) ≥1500 mg or maximum tolerated dose.

Intervention Type: DRUG

Placebo

Matching placebo tablets.

Intervention Type: DRUG

Other Intervention Names

SYR-322; ACTOS®

Eligibility Criteria

Inclusion Criteria

• Has a historical diagnosis of type 2 diabetes mellitus.
• Meets one of the following:

• Has been inadequately controlled (HbA1c between 7% and 10%, inclusive) on a stable dose of greater than or equal to 1500 mg (or maximum tolerated dose) of metformin and 30 mg of pioglitazone
• Has been inadequately controlled (as defined by an HbA1c ≥7.5%) on a combination therapy including metformin and another oral antidiabetic agent (ie, sulfonylureas, rosiglitazone maleate, or pioglitazone 15 mg, etc). Subjects on a combination therapy that included a DPP-4 inhibitor were excluded.
• No treatment with antidiabetic agents other than metformin and pioglitazone.
• Body mass index greater than or equal to 23 kg/m^2 and less than or equal to 45 kg/m^2.
• Fasting plasma C-peptide concentration greater than or equal to 0.8 ng/mL.
• Systolic blood pressure less than 160 mmHg and diastolic pressure less than 100 mmHg.
• Hemoglobin greater than or equal to 12 g/dL for males and greater than or equal to 10 g/dL for females.
• Alanine aminotransferase less than or equal to 2.5 x upper limit of normal.
• Serum creatinine less than 1.5 mg/dL for males and less than 1.4 mg/dL for females.
• Thyroid-stimulating hormone level less than or equal to the upper limit of normal range and the patient is clinically euthyroid.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
• Able and willing to monitor their own blood glucose concentrations with a home glucose monitor.
• No major illness or debility that in the investigator's opinion prohibits the patient from completing the study.

Exclusion Criteria

• Urine albumin/creatinine ratio of greater than 1000 μg/mg.
• History of cancer, other than squamous cell or basal cell carcinoma of the skin, that has not been in full remission for at least 5 years prior to Screening.
• History of bladder cancer.
• History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
• Patients with unexplained microscopic hematuria of greater than +1, confirmed by repeat testing.
• History of treated diabetic gastroparesis.
• History of gastric bypass surgery.
• New York Heart Association Class I-IV heart failure regardless of therapy.
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within the 6 months prior to Screening.
• History of any hemoglobinopathy that may affect determination of glycosylated hemoglobin.
• History of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
• History of a psychiatric disorder that will affect the patient's ability to participate in the study.
• History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
• History of alcohol abuse or substance abuse within the 2 years prior to Screening.
• Receipt of any investigational drug within the 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within the 3 months prior to Screening.
• Prior treatment in an investigational study of alogliptin.
• Hypersensitive to pioglitazone HCl, metformin, alogliptin or other excipients.
• The patient has donated more than 400 mL of blood within the 90 days prior to Screening and Pre-Screening, if applicable.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

VP Biological Sciences

Role: STUDY_DIRECTOR

Takeda

Locations

Birmingham, Alabama, United States

Huntsville, Alabama, United States

Lake Havasu City, Arizona, United States

Little Rock, Arkansas, United States

Foothill Ranch, California, United States

Los Alamitos, California, United States

Los Angeles, California, United States

Pismo Beach, California, United States

San Diego, California, United States

Golden, Colorado, United States

Clearwater, Florida, United States

Hialeah, Florida, United States

Lakeland, Florida, United States

Marianna, Florida, United States

Miami, Florida, United States

North Miami Beach, Florida, United States

Pembroke Pines, Florida, United States

Sebastian, Florida, United States

South Miami, Florida, United States

Tampa, Florida, United States

Winter Park, Florida, United States

Blue Ridge, Georgia, United States

Conyers, Georgia, United States

Decatur, Georgia, United States

Duluth, Georgia, United States

Dunwoody, Georgia, United States

Warner Robins, Georgia, United States

Boise, Idaho, United States

Coeur d'Alene, Idaho, United States

Burr Ridge, Illinois, United States

Chicago, Illinois, United States

Melrose Park, Illinois, United States

Naperville, Illinois, United States

O'Fallon, Illinois, United States

Bloomington, Indiana, United States

Mishawaka, Indiana, United States

Overland Park, Kansas, United States

Marrero, Louisiana, United States

Elkton, Maryland, United States

Rockville, Maryland, United States

Towson, Maryland, United States

Marlborough, Massachusetts, United States

Bay City, Michigan, United States

Saint Clair Shores, Michigan, United States

McCook, Nebraska, United States

Las Vegas, Nevada, United States

Blackwood, New Jersey, United States

Trenton, New Jersey, United States

West Caldwell, New Jersey, United States

Asheboro, North Carolina, United States

Charlotte, North Carolina, United States

Mooresville, North Carolina, United States

Shelby, North Carolina, United States

Sparta, North Carolina, United States

Bismarck, North Dakota, United States

Orrville, Ohio, United States

Norman, Oklahoma, United States

Ashland, Oregon, United States

Aliquippa, Pennsylvania, United States

Altoona, Pennsylvania, United States

Dawningtown, Pennsylvania, United States

Fleetwood, Pennsylvania, United States

Kingston, Pennsylvania, United States

Norristown, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Tipton, Pennsylvania, United States

Florence, South Carolina, United States

Taylors, South Carolina, United States

Williamston, South Carolina, United States

Watertown, South Dakota, United States

Kingsport, Tennessee, United States

Milan, Tennessee, United States

Nashville, Tennessee, United States

Arlington, Texas, United States

Austin, Texas, United States

Colleyville, Texas, United States

El Paso, Texas, United States

Garland, Texas, United States

Houston, Texas, United States

Hurst, Texas, United States

San Antonio, Texas, United States

Seguin, Texas, United States

Hampton, Virginia, United States

Norfolk, Virginia, United States

Richmond, Virginia, United States

Virginia Beach, Virginia, United States

Countries

United States

References

Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011 Dec;13(12):1088-96. doi: 10.1111/j.1463-1326.2011.01463.x.

Reference Type: RESULT

PMID: 21733058 (View on PubMed)

Related Links

http://general.takedapharm.com/content/file/pi.pdf?applicationcode=ab2d7112-8eb3-465a-8fda-35018a9eafb0&fileTypeCode=ACTOSPI

ACTOS® Package Insert

Other Identifiers

2006-006025-73

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1112-3363

Identifier Type: OTHER

Identifier Source: secondary_id

01-06-TL-322OPI-004

Identifier Type: -

Identifier Source: org_study_id