Efficacy of Alogliptin With Pioglitazone (Actos®) in Subjects With Type 2 Diabetes Mellitus

NCT ID: NCT00395512

Last Updated: 2013-03-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 655 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-11-30
• Study Completion Date: 2008-02-29

Brief Summary

The purpose of this study is to evaluate the combination of alogliptin, once daily (QD), and pioglitazone in patients with type 2 diabetes mellitus who are inadequately controlled with diet and exercise alone.

Detailed Description

There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% is type 2. The prevalence of type 2 diabetes varies among racial and ethnic populations and has been shown to correlate with age, obesity, family history, history of gestational diabetes, and physical inactivity. Over the next decade, a marked increase in the number of adults with diabetes mellitus is expected, placing an ever-increasing burden on families and the health care system.

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 reaching 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.

As the rate of newly diagnosed cases of type 2 diabetes mellitus continues to grow, so does the need for products that will provide better glycemic control and improved safety and tolerability. Alogliptin and pioglitazone have complementary actions. Alogliptin inhibits the degradation of glucagon-like peptide-1 by inhibiting the enzyme dipeptidyl peptidase IV, thus augmenting glucose-dependent insulin secretion while pioglitazone is a peripheral and hepatic insulin sensitizer. Given the complementary mechanisms of action of alogliptin (stimulates insulin secretion) and pioglitazone (enhances insulin sensitivity), the addition of combination therapy in treatment naïve type 2 diabetes patients may potentially allow the patients to reach and maintain their glycosylated hemoglobin goal more effectively.

The aim of this study is to evaluate the effectiveness of the combination of alogliptin with pioglitazone in patients who are inadequately controlled on diet and exercise alone. Study participation is anticipated to be approximately 8.5 months.

Conditions

Diabetes Mellitus

Study Design

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

Study Groups

Alogliptin 25 mg QD

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.

Placebo

Intervention Type: DRUG

Matching placebo tablets.

Pioglitazone 30 mg QD

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

Group Type: ACTIVE_COMPARATOR

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Placebo

Intervention Type: DRUG

Matching placebo tablets.

Alogliptin 25 mg QD+ Pioglitazone 30 mg QD

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.

Alogliptin 12.5 mg QD + Pioglitazone 30 mg QD

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

Group Type: ACTIVE_COMPARATOR

Alogliptin

Intervention Type: DRUG

Alogliptin tablets.

Pioglitazone

Intervention Type: DRUG

Pioglitazone tablets.

Interventions

Alogliptin

Alogliptin tablets.

Intervention Type: DRUG

Pioglitazone

Pioglitazone tablets.

Intervention Type: DRUG

Placebo

Matching placebo tablets.

Intervention Type: DRUG

Other Intervention Names

SYR-322; Actos; AD4833

Eligibility Criteria

Inclusion Criteria

• Historical diagnosis of type 2 diabetes.
• Failed treatment with diet and exercise for at least 2 months prior to Screening.
• Is experiencing inadequate glycemic control as defined as glycosylated hemoglobin concentration between 7.5-11%, inclusive.
• Has received any antidiabetic therapy for less than 7 days within 3 months prior to Screening.
• Has a body mass index greater than or equal to 23 kg/m2 and less than or equal to45 kg/m2.
• Fasting C-peptide greater than or equal to 0.8 ng per mL.
• Regular use of other, non-excluded medications is allowed if participant is on a stable dose for at least 4 weeks prior to Screening.
• 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.
• Must be willing and able to monitor their blood concentrations with a home glucose monitor.

Exclusion Criteria

• Systolic blood pressure greater than or equal to 160 mmHg and diastolic blood pressure greater than or equal to 100 mmHg.
• Hemoglobin less than or equal to 12 g per dL for males and less than or equal to 10 g per dL for females.
• Alanine aminotransferase greater than or equal to 2.5times the upper limit of normal.
• Serum creatinine greater than 2.0 mg per dL.
• Thyroid stimulating hormone level greater than the upper limit of normal range.
• Major illness or debility that in the investigator's opinion prohibits the subject from completing the study.
• Urine albumin to creatinine ratio of greater than 1000 ug per mg at Screening. If elevated, the subject may be rescreened within 1 week.
• 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 laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening.
• History of gastroparesis.
• Has New York Heart Association Class I to IV heart failure regardless of therapy.
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 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 participant's ability to participate in the study.
• History of angioedema in association with use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor inhibitors.
• Any alteration in angiotensin-II receptor inhibitors within 2 months prior to Randomization, if applicable.
• History of alcohol (defined as regular or daily consumption of more than 4 alcoholic drinks per day) or substance abuse (defined as illicit drug use) within 2 years prior to Screening.
• Received 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.
• Previously participated in an investigational study of SYR-322.
• Glycosylated hemoglobin concentration between 7.5-11%, inclusive, and a fasting plasma glucose less than 310 mg per dL.
• At least 75% compliant with the single-blind placebo regimen during the run-in/stabilization period.

• 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

Columbiana, Alabama, United States

Hueytown, Alabama, United States

Huntsville, Alabama, United States

Northport, Alabama, United States

Tucson, Arizona, United States

Jonesboro, Arkansas, United States

Little Rock, Arkansas, United States

Searcy, Arkansas, United States

Foothill Ranch, California, United States

Irvine, California, United States

Northridge, California, United States

San Diego, California, United States

San Mateo, California, United States

Santa Monica, California, United States

Jacksonville, Florida, United States

Melbourne, Florida, United States

Miami, Florida, United States

Port Charlotte, Florida, United States

Sebastian, Florida, United States

South Miami, Florida, United States

Winter Haven, Florida, United States

Augusta, Georgia, United States

Barnesville, Georgia, United States

Columbus, Georgia, United States

Savannah, Georgia, United States

Chicago, Illinois, United States

Libertyville, Illinois, United States

South Bend, Indiana, United States

Bossier City, Louisiana, United States

Elkton, Maryland, United States

Prince Frederick, Maryland, United States

Towson, Maryland, United States

North Dartmouth, Massachusetts, United States

Bay City, Michigan, United States

Benzonia, Michigan, United States

Portage, Michigan, United States

Saint Clair Shores, Michigan, United States

Picayune, Mississippi, United States

St Louis, Missouri, United States

Billings, Montana, United States

Las Vegas, Nevada, United States

Elizabeth, New Jersey, United States

Hamilton, New Jersey, United States

Cicero, New York, United States

Charlotte, North Carolina, United States

Mooresville, North Carolina, United States

Northeast, North Dakota, United States

Franklin, Ohio, United States

Ashland, Oregon, United States

Altoona, Pennsylvania, United States

Fleetwood, Pennsylvania, United States

Harleysville, Pennsylvania, United States

Havertown, Pennsylvania, United States

Norristown, Pennsylvania, United States

Northern Cambria, Pennsylvania, United States

Penndel, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Charleston, South Carolina, United States

Florence, South Carolina, United States

Orangeburg, South Carolina, United States

Taylors, South Carolina, United States

Williamston, South Carolina, United States

Morristown, Tennessee, United States

Arlington, Texas, United States

Colleyville, Texas, United States

Conroe, Texas, United States

Corpus Christi, Texas, United States

Dallas, Texas, United States

Euless, Texas, United States

Fort Worth, Texas, United States

Garland, Texas, United States

Houston, Texas, United States

Katy, Texas, United States

San Antonio, Texas, United States

Seguin, Texas, United States

Sugarland, Texas, United States

Tomball, Texas, United States

Ogden, Utah, United States

Arlington, Virginia, United States

Norfolk, Virginia, United States

Richmond, Virginia, United States

Lewisburg, West Virginia, United States

Milwaukee, Wisconsin, United States

Cap. Fed., Buenos Aires, Argentina

Chacabuco, Buenos Aires, Argentina

La Plata, Buenos Aires, Argentina

Mar del Plata, Buenos Aires, Argentina

Morón, Buenos Aires, Argentina

Córdoba, , Argentina

Kingswood, New South Wales, Australia

Fitzroy, Victoria, Australia

Frankston, Victoria, Australia

Fortaleza, Ceará, Brazil

Goiás, Goiás, Brazil

Curitiba, Paraná, Brazil

Belém, Pará, Brazil

Maringá, RP, Brazil

Marília, São Paulo, Brazil

Mogi das Cruzes, São Paulo, Brazil

Pleven, , Bulgaria

Santiago, , Chile

Slavonski Brod, , Croatia

Pärnu, , Estonia

Guatemala City, , Guatemala

Budapest, , Hungary

Eger, , Hungary

Gyula, , Hungary

Makó, , Hungary

Nyíregyháza, , Hungary

Pécs, , Hungary

Hyderabad, Andhra Pradesh, India

Bangalore, Karnataka, India

Aurangabad, Maharashtra, India

Mumbai, Maharashtra, India

Nagpur, Maharashtra, India

Chennai, Tamil Nadu, India

Hadera, , Israel

Haifa, , Israel

Holon, , Israel

Jaffa Tel Aviv, , Israel

Jerusalem, , Israel

Nahariya, , Israel

Riga, , Latvia

Kaunas, , Lithuania

Kėdainiai, , Lithuania

Aguascalientes, , Mexico

Mexico City, , Mexico

Monterrey, , Mexico

Christchurch, , New Zealand

Hamilton, , New Zealand

Bialystok, , Poland

Bytom, , Poland

Gdansk, , Poland

Gniewkowo, , Poland

Kamieniec Ząbkowicki, , Poland

Krakow, , Poland

Łęczyca, , Poland

Brasov, , Romania

Bucharest, , Romania

Galati, , Romania

Kazan', , Russia

Moscow, , Russia

Yekaterinburg, , Russia

Belgrade, , Serbia

Kragujevac, , Serbia

Niš, , Serbia

Interna Klinika II, Nitra Region, Slovakia

Banska Bysterica, , Slovakia

Lučenec, , Slovakia

Riverside, , Slovakia

Šahy, , Slovakia

Port Elizabeth, Eastern Cape, South Africa

Johannesburg, Gauteng, South Africa

Durban, KwaZulu-Natal, South Africa

East Lynne, Pretoria, South Africa

Bellville, Western Province, South Africa

Cape Town, Western Province, South Africa

Dnipropetrovsk, , Ukraine

Kharkiv, , Ukraine

Lviv, , Ukraine

Odesa, , Ukraine

Countries

United States; Argentina; Australia; Brazil; Bulgaria; Chile; Croatia; Estonia; Guatemala; Hungary; India; Israel; Latvia; Lithuania; Mexico; New Zealand; Poland; Romania; Russia; Serbia; Slovakia; South Africa; Ukraine

References

Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes. Diabetes Care. 2010 Nov;33(11):2406-8. doi: 10.2337/dc10-0159. Epub 2010 Aug 19.

Reference Type: RESULT

PMID: 20724648 (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

2006-005492-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1113-8616

Identifier Type: REGISTRY

Identifier Source: secondary_id

01-06-TL-322OPI-002

Identifier Type: -

Identifier Source: org_study_id