Study of Alogliptin Combined With Pioglitazone in Subjects With Type 2 Diabetes Mellitus

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Determine the Efficacy and Safety of SYR110322 (SYR-322) When Used in Combination With Pioglitazone in Subjects With Type 2 Diabetes Mellitus

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

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Drug: Pioglitazone; Drug: Alogliptin and pioglitazone; Drug: Alogliptin and pioglitazone

Detailed Description

There are approximately 19 million people in the United States who have been diagnosed with diabetes mellitus, of which 90% to 95% are 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.

Takeda is developing SYR-322 (alogliptin) for the improvement of glycemic control in patients with type 2 diabetes mellitus. Alogliptin is an inhibitor of the dipeptidyl peptidase IV enzyme. Dipeptidyl peptidase IV is thought to be primarily responsible for the degradation of 2 peptide hormones released in response to nutrient ingestion. It is expected that inhibition of dipeptidyl peptidase IV will improve glycemic (glucose) control in patients with type 2 diabetes.

The aim of the current study is to evaluate the efficacy of alogliptin in combination with pioglitazone in subjects who are inadequately controlled on a thiazolidinedione (pioglitazone or rosiglitazone) alone or in combination with metformin or a sulfonylurea. Individuals who participate in this study will be required to commit to a screening visit and up to 14 additional visits at the study center. Study participation is anticipated to be about 34 weeks (or 8.5 months).

• Study Type: Interventional
• Enrollment (Actual): 493
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Multiple Cities, Argentina
• Australia
  • Multiple Cities, Australia
• Brazil
  • Multiple Cities, Brazil
• Czech Republic
  • Multiple Cities, Czech Republic
• Germany
  • Multiple Cities, Germany
• Guatemala
  • Multiple Cities, Guatemala
• Hungary
  • Multiple Cities, Hungary
• India
  • Multiple Cities, India
• Mexico
  • Multiple Cities, Mexico
• Netherlands
  • Multiple Cities, Netherlands
• New Zealand
  • Multiple Cities, New Zealand
• Peru
  • Multiple Cities, Peru
• South Africa
  • Multiple Cities, South Africa
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
  • California
    • Anaheim, California, United States
    • Artesia, California, United States
    • Fresno, California, United States
    • Mission Viejo, California, United States
    • Northridge, California, United States
    • Orange, California, United States
    • San Diego, California, United States
    • Walnut Creek, California, United States
  • Colorado
    • Colorado Springs, Colorado, United States
    • Denver, Colorado, United States
  • Connecticut
    • Norwalk, Connecticut, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Florida
    • Clearwater, Florida, United States
    • Cocoa Beach, Florida, United States
    • Hollywood, Florida, United States
    • Kissimmee, Florida, United States
    • Longwood, Florida, United States
    • New Port Richey, Florida, United States
    • Ocala, Florida, United States
    • Ocoee, Florida, United States
    • St. Cloud, Florida, United States
    • Tampa, Florida, United States
  • Georgia
    • Lawrenceville, Georgia, United States
  • Hawaii
    • Honolulu, Hawaii, United States
  • Idaho
    • Idaho Falls, Idaho, United States
  • Illinois
    • Chicago, Illinois, United States
  • Indiana
    • Avon, Indiana, United States
    • Elkhart, Indiana, United States
    • Evansville, Indiana, United States
    • Lafayette, Indiana, United States
  • Kentucky
    • Erlanger, Kentucky, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Sudbury, Massachusetts, United States
  • Missouri
    • Chesterfield, Missouri, United States
    • St. Louis, Missouri, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • New Jersey
    • Berlin, New Jersey, United States
  • North Carolina
    • Burlington, North Carolina, United States
    • Charlotte, North Carolina, United States
    • Hickory, North Carolina, United States
    • Morehead City, North Carolina, United States
    • Pinehurst, North Carolina, United States
    • Wilmington, North Carolina, United States
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Dayton, Ohio, United States
  • Oklahoma
    • Tulsa, Oklahoma, United States
  • Oregon
    • Medford, Oregon, United States
  • Pennsylvania
    • Lansdale, Pennsylvania, United States
    • West Grove, Pennsylvania, United States
  • South Carolina
    • Charleston, South Carolina, United States
    • Columbia, South Carolina, United States
    • Simpsonville, South Carolina, United States
  • Tennessee
    • Bristol, Tennessee, United States
    • Cookeville, Tennessee, United States
    • Milan, Tennessee, United States
  • Texas
    • Corpus Christi, Texas, United States
    • Dallas, Texas, United States
    • San Antonio, Texas, United States
    • Temple, Texas, United States
    • Texarkana, Texas, United States
  • Vermont
    • Burlington, Vermont, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Diagnosis of type 2 diabetes mellitus currently treated with a thiazolidinedione either alone or in combination with metformin or a sulfonylurea but who are experiencing inadequate glycemic control. The subject should have received the thiazolidinedione therapy (rosiglitazone or pioglitazone) either alone or in combination with metformin or a sulfonylurea for at least the 3 months prior to Screening and must have been on a stable dose for all their antidiabetic treatments for at least the month prior to Screening.
• No treatment with antidiabetic agents other than a thiazolidinedione alone or in combination with either metformin or a sulfonylurea within the 3 months prior to Screening. (Exception: if a subject has received other antidiabetic therapy for less than 7 days within the 3 months prior to Screening.)
• Body mass index greater than or equal to 23 kg/m2 and less than or equal to 45 kg/m2
• Fasting C-peptide concentration greater than or equal to 0.8 ng per mL. (If this screening criterion is not met, the subject still qualifies if C-peptide is greater than or equal to 1.5 ng per mL after a challenge test.)
• Glycosylated hemoglobin concentration between 7.0% and 10.0%, inclusive.
• If regular use of other, non-excluded medications, must be on a stable dose for at least the 4 weeks prior to Screening. However, as needed use of prescription or over-the-counter medications is allowed at the discretion of the investigator.
• Systolic blood pressure less than or equal to 180 mm Hg and diastolic pressure less than or equal to 110 mm Hg.
• Hemoglobin greater than or equal to 12 g per dL for males and greater than or equal to10 g per dL for females.
• Alanine aminotransferase less than or equal to 2.5 times the upper limit of normal.
• Serum creatinine less than or equal to 2.0 mg per dL.
• Thyroid-stimulating hormone level less than or equal to the upper limit of the normal range and the subject is clinically euthyroid.
• Neither pregnant nor lactating.
• Female subjects of childbearing potential must be practicing adequate contraception. Adequate contraception must be practiced for the duration of participation in 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 subject from completing the study.
• Able and willing to provide written informed consent.

Exclusion Criteria

• Urine albumin to creatinine ratio of greater than 1000 μg 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. (A history of treated cervical intraepithelial neoplasia I or cervical intraepithelial neoplasia II is allowed.)
• History of laser treatment for proliferative diabetic retinopathy within the 6 months prior to Screening.
• History of treated diabetic gastric paresis.
• New York Heart Association Class III or IV heart failure regardless of therapy. Currently treated subjects who are stable at Class I or II are candidates for the study.
• 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 subject'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 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.

• Excluded Medications:

  • Treatment with antidiabetic agents other than a thiazolidinedione alone or in combination with either metformin or a sulfonylurea is not allowed within the 3 months prior to Screening and through the completion of the end-of-treatment/early termination procedures.
  • Treatment with weight-loss drugs, any investigational antidiabetics, or oral or systemically injected glucocorticoids is not allowed from 3 months prior to randomization through the completion of the end-of-treatment/early termination procedures. Inhaled corticosteroids are allowed.

Subjects must not take any medications, including over-the-counter products, without first consulting with the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Placebo	Drug: Pioglitazone; Alogliptin placebo-matching tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks; Other Names: Actos; AD-4833
EXPERIMENTAL: Alogliptin 12.5 mg QD	Drug: Alogliptin and pioglitazone; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks; Other Names: Actos; SYR-322; SYR110322; AD-4833; Pioglitazone; Alogliptin; Drug: Alogliptin and pioglitazone; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks; Other Names: Actos; SYR-322; SYR110322; AD-4833; Pioglitazone; Alogliptin
EXPERIMENTAL: Alogliptin 25 mg QD	Drug: Alogliptin and pioglitazone; Alogliptin 12.5 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks; Other Names: Actos; SYR-322; SYR110322; AD-4833; Pioglitazone; Alogliptin; Drug: Alogliptin and pioglitazone; Alogliptin 25 mg, tablets, orally, once daily and pioglitazone 30 mg or 45 mg, tablets, orally, once daily for up to 26 weeks; Other Names: Actos; SYR-322; SYR110322; AD-4833; Pioglitazone; Alogliptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 26.	The change in the value of glycosylated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 26 or final visit and glycosylated hemoglobin collected at baseline.	Baseline and Week 26.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (Week 8).	The change between the value of fasting plasma glucose collected at week 8 and fasting plasma glucose collected at baseline.	Baseline and Week 8.
Change From Baseline in Fasting Plasma Glucose (Week 12).	The change between the value of fasting plasma glucose collected at week 12 and fasting plasma glucose collected at baseline.	Baseline and Week 12.
Change From Baseline in Fasting Plasma Glucose (Week 16).	The change between the value of fasting plasma glucose collected at week 16 and fasting plasma glucose collected at baseline.	Baseline and Week 16.
Change From Baseline in Fasting Plasma Glucose (Week 20).	The change between the value of fasting plasma glucose collected at week 20 and fasting plasma glucose collected at baseline.	Baseline and Week 20.
Change From Baseline in Fasting Plasma Glucose (Week 4).	The change between the value of fasting plasma glucose collected at week 4 and fasting plasma glucose collected at baseline.	Baseline and Week 4.
Change From Baseline in Glycosylated Hemoglobin (Week 4).	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 4 and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 4.
Change From Baseline in Glycosylated Hemoglobin (Week 8).	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 8 and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 8.
Change From Baseline in Glycosylated Hemoglobin (Week 12).	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 12 and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 12.
Change From Baseline in Glycosylated Hemoglobin (Week 16).	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 16 and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 16.
Change From Baseline in Glycosylated Hemoglobin (Week 20).	The change in the value of Glycosylated Hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) collected at week 20 and Glycosylated Hemoglobin collected at baseline.	Baseline and Week 20.
Change From Baseline in Fasting Plasma Glucose (Week 1).	The change between the value of fasting plasma glucose collected at final visit or week 1 and fasting plasma glucose collected at baseline.	Baseline and Week 1.
Change From Baseline in Fasting Plasma Glucose (Week 2).	The change between the value of fasting plasma glucose collected at week 2 and fasting plasma glucose collected at baseline.	Baseline and Week 2.
Change From Baseline in Fasting Plasma Glucose (Week 26).	The change between the value of fasting plasma glucose collected at week 26 or final visit and fasting plasma glucose collected at baseline.	Baseline and Week 26.
Number of Participants With Marked Hyperglycemia (Fasting Plasma Glucose ≥ 200 mg Per dL).	The number of participants with a fasting plasma glucose value greater than or equal to 200 mg per dL during the 26 week study.	26 Weeks.
Number of Participants Requiring Rescue.	The number of participants requiring rescue for failing to achieve pre-specified glycemic targets during the 26 week study.	26 Weeks.
Change From Baseline in Fasting Proinsulin (Week 4).	The change between the value of fasting proinsulin collected at week 4 and fasting proinsulin collected at baseline.	Baseline and Week 4.
Change From Baseline in Fasting Proinsulin (Week 8).	The change between the value of fasting proinsulin collected at week 8 and fasting proinsulin collected at baseline.	Baseline and Week 8.
Change From Baseline in Fasting Proinsulin (Week 12).	The change between the value of fasting proinsulin collected at week 12 and fasting proinsulin collected at baseline.	Baseline and Week 12.
Change From Baseline in Fasting Proinsulin (Week 16).	The change between the value of fasting proinsulin collected at week 16 and fasting proinsulin collected at baseline.	Baseline and Week 16.
Change From Baseline in Fasting Proinsulin (Week 20).	The change between the value of fasting proinsulin collected at week 20 and fasting proinsulin collected at baseline.	Baseline and Week 20.
Change From Baseline in Fasting Proinsulin (Week 26).	The change between the value of fasting proinsulin collected at week 26 or final visit and fasting proinsulin collected at baseline.	Baseline and Week 26.
Change From Baseline in Insulin (Week 4).	The change between the value of insulin collected at week 4 and insulin collected at baseline.	Baseline and Week 4.
Change From Baseline in Insulin (Week 8).	The change between the value of insulin collected at week 8 and insulin collected at baseline.	Baseline and Week 8.
Change From Baseline in Insulin (Week 12).	The change between the value of insulin collected at week 12 and insulin collected at baseline.	Baseline and Week 12.
Change From Baseline in Insulin (Week 16).	The change between the value of insulin collected at week 16 and insulin collected at baseline.	Baseline and Week 16.
Change From Baseline in Insulin (Week 20).	The change between the value of insulin collected at week 20 and insulin collected at baseline.	Baseline and Week 20.
Change From Baseline in Insulin (Week 26).	The change between the value of insulin collected at week 26 and insulin collected at baseline.	Baseline and Week 26.
Change From Baseline in Proinsulin/Insulin Ratio (Week 4).	The change between the ratio value of proinsulin and insulin collected at week 4 and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 4.
Change From Baseline in Proinsulin/Insulin Ratio (Week 8).	The change between the ratio value of proinsulin and insulin collected at week 8 and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 8.
Change From Baseline in Proinsulin/Insulin Ratio (Week 12).	The change between the ratio value of proinsulin and insulin collected at week 12 and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 12.
Change From Baseline in Proinsulin/Insulin Ratio (Week 16).	The change between the ratio value of proinsulin and insulin collected at week 16 and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 16.
Change From Baseline in Proinsulin/Insulin Ratio (Week 20).	The change between the ratio value of proinsulin and insulin collected at week 20 and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 20.
Change From Baseline in Proinsulin/Insulin Ratio (Week 26).	The change between the ratio value of proinsulin and insulin collected at week 26 or final visit and the ratio value of proinsulin and insulin collected at baseline.	Baseline and Week 26.
Change From Baseline in C-peptide (Week 4).	The change between the value of C-peptide collected at week 4 and C-peptide collected at baseline.	Baseline and Week 4.
Change From Baseline in C-peptide (Week 8).	The change between the value of C-peptide collected at week 8 and C-peptide collected at baseline.	Baseline and Week 8.
Change From Baseline in C-peptide (Week 12).	The change between the value of C-peptide collected at week 12 and C-peptide collected at baseline.	Baseline and Week 12.
Change From Baseline in C-peptide (Week 16).	The change between the value of C-peptide collected at week 16 and C-peptide collected at baseline.	Baseline and Week 16.
Change From Baseline in C-peptide (Week 20).	The change between the value of C-peptide collected at week 20 and C-peptide collected at baseline.	Baseline and Week 20.
Change From Baseline in C-peptide (Week 26).	The change between the value of C-peptide collected at week 26 or final visit and C-peptide collected at baseline.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin ≤ 6.5%.	The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 6.5% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin ≤ 7.0%.	The number of participants with a value for the percentage of glycosylated hemoglobin less (the percentage of hemoglobin that is bound to glucose) than or equal to 7.0% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin ≤ 7.5%.	The number of participants with a value for the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) less than or equal to 7.5% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 0.5%.	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 0.5% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.0%.	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.0% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 1.5%.	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 1.5% during the 26 week study.	Baseline and Week 26.
Number of Participants With Glycosylated Hemoglobin Decrease From Baseline ≥ 2.0%.	The number of participants with a decrease from baseline in the percentage of glycosylated hemoglobin (the percentage of hemoglobin that is bound to glucose) greater than or equal to 2.0% during the 26 week study.	Baseline and Week 26.
Change From Baseline in Body Weight (Week 8).	The change between Body Weight measured at week 8 and Body Weight measured at baseline.	Baseline and Week 8.
Change From Baseline in Body Weight (Week 12).	The change between Body Weight measured at week 12 and Body Weight measured at baseline.	Baseline and Week 12.
Change From Baseline in Body Weight (Week 20).	The change between Body Weight measured at week 20 and Body Weight measured at baseline.	Baseline and Week 20.
Change From Baseline in Body Weight (Week 26).	The change between Body Weight measured at week 26 or final visit and Body Weight measured at baseline.	Baseline and Week 26.

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009 Oct;25(10):2361-71. doi: 10.1185/03007990903156111.
• Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q. Alogliptin use in elderly people: a pooled analysis from phase 2 and 3 studies. J Am Geriatr Soc. 2009 Nov;57(11):2011-9. doi: 10.1111/j.1532-5415.2009.02484.x. Epub 2009 Sep 30.

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (ACTUAL): August 1, 2007
• Study Completion (ACTUAL): August 1, 2007

Study Registration Dates

• First Submitted: February 1, 2006
• First Submitted That Met QC Criteria: February 1, 2006
• First Posted (ESTIMATE): February 3, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): February 3, 2012
• Last Update Submitted That Met QC Criteria: February 1, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: Drug Therapy; Dyslipidemia; Type II Diabetes; Diabetes Mellitus; Glucose Metabolism Disorder; Dysmetabolic Syndrome; Lipoatrophic
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Pioglitazone; Alogliptin
• Other Study ID Numbers: SYR-322-TZD-009; 2005-004669-40 (EUDRACT_NUMBER); U1111-1113-8552 (REGISTRY: WHO)