Efficacy and Safety of Alogliptin Combined With Pioglitazone in Treating Subjects With Type 2 Diabetes Mellitus.

NCT ID: NCT00328627

Last Updated: 2013-04-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1554 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-31
• Study Completion Date: 2008-03-31

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of alogliptin, once daily (QD), taken in combination with pioglitazone in adults with type 2 diabetes mellitus.

Detailed Description

Over the past 30 years, the prevalence of diabetes has increased dramatically throughout the world due to population growth, aging, urbanization, increasing obesity, and physical inactivity. The total number of people with type 2 diabetes mellitus is projected to rise from 171 million in 2000 to 366 million in 2030. The incidence of type 2 diabetes mellitus in the United States alone is expected to increase from approximately 17 to 30.3 million by the year 2030. Type 2 diabetes mellitus is associated with a number of long-term microvascular and macrovascular complications associated with a reduced quality of life and increased morbidity and mortality. It is anticipated that the increasing incidence of type 2 diabetes mellitus will place an ever-increasing burden on families, increase national expenditures for health care services, and decrease worker productivity.

Current pharmacologic interventions for type 2 diabetes mellitus include a diverse range of antidiabetic medications with different mechanisms of action including insulin and insulin analogues, sulfonylureas, metformin, meglitinides, thiazolidinediones, inhibitors of alpha-glucosidase, analogs of glucagon-like peptide-1 and synthetic analogues of human amylin. Despite the variety of medications, many have clinically important or potentially life-threatening side effects, restricted use in many subpopulations, concerns with long-term tolerability, and challenges related to compliance due to side effects and route of administration. All of these reasons contribute to the difficulties patients have achieving the target glycosylated hemoglobin level less than 7%.

SYR-322 (alogliptin) is a selective, orally available inhibitor of the dipeptidyl peptidase-4 enzyme. Dipeptidyl peptidase-4 enzyme is thought to be primarily responsible for the in vivo degradation of 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 beta cells to stimulate glucose-dependent insulin secretion as well as regulating beta cell proliferation and cytoprotection. Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits gastric emptying, glucagon secretion, and food intake. Glucose-dependent insulinotropic peptide has been shown to enhance insulin secretion by direct interaction with a glucose-dependent insulinotropic peptide -specific receptor on islet beta cells. The glucose-lowering actions of glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, are preserved in patients with type 2 diabetes mellitus.

Pioglitazone (ACTOS®) is a thiazolidinedione developed by Takeda Chemical Industries, Ltd. (Osaka, Japan) that is approved for the treatment of type 2 diabetes mellitus. Pioglitazone is a selective peroxisome proliferator-activated receptor-gamma agonist that decreases insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.

Given the complementary mechanisms of action of alogliptin (stimulation of insulin secretion) and pioglitazone (enhancement of insulin sensitivity), the goal of this study is to evaluate the efficacy of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on metformin. Study participation is anticipated to be approximately 7 months.

Conditions

Type 2 Diabetes Mellitus

Study Design

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

Study Groups

Placebo

Alogliptin placebo-matching tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.

Group Type: PLACEBO_COMPARATOR

Alogliptin placebo

Intervention Type: DRUG

Alogliptin placebo-matching tablets.

Pioglitazone placebo

Intervention Type: DRUG

Pioglitazone placebo-matching tablets.

Alogliptin 12.5 + Placebo

Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone placebo

Intervention Type: DRUG

Pioglitazone placebo-matching tablets.

Alogliptin 25 + Placebo

Alogliptin 25 mg, tablets, orally, once daily and pioglitazone placebo-matching tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone placebo

Intervention Type: DRUG

Pioglitazone placebo-matching tablets.

Placebo + Pioglitazone 15

Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: ACTIVE_COMPARATOR

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 12.5 + Pioglitazone 15

Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 25 + Pioglitazone 15

Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 15 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Placebo + Pioglitazone 30

Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: ACTIVE_COMPARATOR

Alogliptin placebo

Intervention Type: DRUG

Alogliptin placebo-matching tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 12.5 + Pioglitazone 30

Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 25 + Pioglitazone 30

Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Placebo + Pioglitazone 45

Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: ACTIVE_COMPARATOR

Alogliptin placebo

Intervention Type: DRUG

Alogliptin placebo-matching tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 12.5 + Pioglitazone 45

Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Alogliptin 25 + Pioglitazone 45

Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 45 mg, tablets, orally, once daily for up to 26 weeks.

Group Type: EXPERIMENTAL

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Interventions

Alogliptin

Alogliptin tablets.

Intervention Type: DRUG

Alogliptin placebo

Alogliptin placebo-matching tablets.

Intervention Type: DRUG

Pioglitazone

Pioglitazone tablets.

Intervention Type: DRUG

Pioglitazone placebo

Pioglitazone placebo-matching tablets.

Intervention Type: DRUG

Other Intervention Names

SYR-322; ACTOS®

Eligibility Criteria

Inclusion Criteria

• Men or women with a historical diagnosis of type 2 diabetes mellitus who were treated with metformin greater than or equal to 1500 mg alone but were experiencing inadequate glycemic control.
• A stable dose of metformin of greater than or equal to 1500 mg or maximum tolerated dose.
• No treatment with antidiabetic agents other than metformin within the 2 months prior to Screening.
• A body mass index greater than or equal to 23 kg/m^2 and less than or equal to 45 kg/m^2.
• Fasting C-peptide greater than or equal to 0.8 ng/mL.
• Regular use of other, non-excluded medications was allowed if a stable dose had been established for at least 4 weeks prior to Screening.
• Systolic blood pressure less than or equal to 160 mmHg and diastolic pressure less than or equal to 100 mmHg.
• Hemoglobin greater than or equal to 12 g/dL for men and greater than or equal to 10 g/dL for women.
• Alanine aminotransferase less than or equal to 2.5 times the upper limit of normal.
• Serum creatinine less than 1.5 mg/dL for men and less than 1.4 mg/dL for women.
• Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the subject was 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 prohibited the patient from completing the study.

Exclusion Criteria

• Urine albumin/creatinine ratio greater than 113 mg/mmol at Screening.
• A history of cancer, other than squamous cell or basal cell carcinoma of the skin, that had not been in full remission for at least 5 years prior to Screening.
• A history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
• A history of treated diabetic gastroparesis.
• New York Heart Association Class III or 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.
• History of infection with hepatitis B, hepatitis C or human immunodeficiency virus.
• History of a psychiatric disorder that could have affected 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.
• A history of alcohol or substance abuse within 2 years prior to Screening.
• Receipt of any investigational drug within 30 days prior to Screening or a history of receipt of an investigational antidiabetic drug within 3 months prior to Screening.
• Previous participation in an investigational study of alogliptin.
• Hypersensitive to pioglitazone, alogliptin, or other excipients.

• 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

Columbiana, Alabama, United States

Huntsville, Alabama, United States

Phoenix, Arizona, United States

Little Rock, Arkansas, United States

Searcy, Arkansas, United States

Sherwood, Arkansas, United States

Burbank, California, United States

Foothill Ranch, California, United States

Irvine, California, United States

Sacramento, California, United States

San Diego, California, United States

Temecula, California, United States

Tustin, California, United States

Colorado Springs, Colorado, United States

Washington D.C., District of Columbia, United States

Hollywood, Florida, United States

Kissimmee, Florida, United States

Miami, Florida, United States

New Port Richey, Florida, United States

Pembroke Pines, Florida, United States

Pinellas Park, Florida, United States

Sarasota, Florida, United States

Vero Beach, Florida, United States

Atlanta, Georgia, United States

Roswell, Georgia, United States

Savannah, Georgia, United States

Warner Robins, Georgia, United States

Chicago, Illinois, United States

Peoria, Illinois, United States

Lafayette, Indiana, United States

South Bend, Indiana, United States

Waterloo, Iowa, United States

Munfordville, Kentucky, United States

Baton Rouge, Louisiana, United States

Marrero, Louisiana, United States

Elkridge, Maryland, United States

Prince Frederick, Maryland, United States

Towson, Maryland, United States

Marlborough, Massachusetts, United States

Ann Arbor, Michigan, United States

Cadillac, Michigan, United States

Detroit, Michigan, United States

Livonia, Michigan, United States

Kansas City, Missouri, United States

North Las Vegas, Nevada, United States

Blackwood, New Jersey, United States

Trenton, New Jersey, United States

New York, New York, United States

Charlotte, North Carolina, United States

Statesville, North Carolina, United States

Gallipolis, Ohio, United States

Marion, Ohio, United States

Clinton, Oklahoma, United States

Oklahoma City, Oklahoma, United States

Tulsa, Oklahoma, United States

Allentown, Pennsylvania, United States

Altoona, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Pittsburgh, Pennsylvania, United States

Alcoa, Tennessee, United States

Milan, Tennessee, United States

Morristown, Tennessee, United States

Arlington, Texas, United States

Carrollton, Texas, United States

Dallas, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

San Antonio, Texas, United States

Temple, Texas, United States

Salt Lake City, Utah, United States

Burlington, Vermont, United States

Multiple Cities, , Australia

Multiple Cities, , Brazil

Multiple Cities, , Bulgaria

Multiple Cities, , Chile

Multiple Cities, , Croatia

Multiple Cities, , Estonia

Multiple Cities, , Guatemala

Multiple Cities, , India

Multiple Cities, , Israel

Multiple Cities, , Latvia

Multiple Cities, , Mexico

Multiple Cities, , New Zealand

Multiple Cities, , Peru

Multiple Cities, , Romania

Multiple Cities, , Russia

Multiple Cities, , Serbia

Multiple Cities, , South Africa

Multiple Cities, , Ukraine

Countries

United States; Australia; Brazil; Bulgaria; Chile; Croatia; Estonia; Guatemala; India; Israel; Latvia; Mexico; New Zealand; Peru; Romania; Russia; Serbia; South Africa; Ukraine

References

DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012 May;97(5):1615-22. doi: 10.1210/jc.2011-2243. Epub 2012 Mar 14.

Reference Type: RESULT

PMID: 22419732 (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

2006-000694-30

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1113-8587

Identifier Type: REGISTRY

Identifier Source: secondary_id

01-05-TL-322OPI-001

Identifier Type: -

Identifier Source: org_study_id