• Change from Baseline in Glycosylated Hemoglobin. [ Time Frame: Weeks 4, 8, 12, 16, 20, 26, 39, 65, 78, and 91. ] [ Designated as safety issue: No ]
• Change from Baseline in Fasting Plasma Glucose. [ Time Frame: Weeks 2, 4, 8, 12, 16, 20, 26, 39, 52, 65, 78, 91, and 104. ] [ Designated as safety issue: No ]
• Incidence of Glycosylated Hemoglobin less than or equal to 6.5% [ Time Frame: Weeks 26, 52, 78, and 104. ] [ Designated as safety issue: No ]
• Incidence of Glycosylated Hemoglobin less than to 7.0% [ Time Frame: Weeks 26, 52, 78, and 104. ] [ Designated as safety issue: No ]
• Change from Baseline in Body Weight [ Time Frame: Weeks 12, 26, 39, 52, 65, 78, 91, and 104. ] [ Designated as safety issue: No ]

The purpose of this study is to determine the safety and effectiveness of adding alogliptin compared to glipizide with metformin in diabetic subjects.

For patients diagnosed with type 2 diabetes mellitus, metformin is the usual first-line therapy in addition to diet control and exercise. For those patients with inadequate glycemic control with metformin monotherapy or experiencing serious side effects of metformin, sulfonylurea is a popular choice as a second-line oral antidiabetic treatment.

Alogliptin is a dipeptidyl peptidase-4 inhibitor currently being developed by Takeda for use in patients with type 2 diabetes mellitus.

This study is designed to further explore the durability of efficacy and safety of alogliptin once daily (QD) compared to glipizide in type 2 diabetes mellitus subjects whose blood sugar level is inadequately controlled with metformin therapy.

The duration of this study will be approximately 2 years.

• Drug: Alogliptin and metformin
  Alogliptin 12.5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
  Other Names:

  • SYR-322
  • Glucophage
• Drug: Alogliptin and metformin
  Alogliptin 25 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
  Other Names:

  • SYR-322
  • Glucophage
• Drug: Glipizide and metformin
  Glipizide 5 mg, tablets, orally, once daily and the maximum tolerated dose of metformin (1500 mg to 3300 mg daily) for up to 104 weeks.
  Other Names:

  • SYR-322
  • Glucotrol
  • Glucophage

• Alogliptin 12.5 mg QD: Experimental
  and maximum tolerated dose of metformin
  Intervention: Drug: Alogliptin and metformin
• Alogliptin 25 mg QD: Experimental
  and maximum tolerated dose of metformin
  Intervention: Drug: Alogliptin and metformin
• Glipizide 5 mg QD: Active Comparator
  and maximum tolerated dose of metformin
  Intervention: Drug: Glipizide and metformin

Inclusion Criteria:

• Has a diagnosis of type 2 diabetes mellitus.

• Must meet one of the following:

  • Has been inadequately controlled on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose) of metformin for at least 2 months prior to Screening.
  • Has been inadequately controlled (as defined by a glycosylated hemoglobin 7.5 10%, inclusive) on metformin <1500 mg without documented maximum tolerated dose.
• No treatment with antidiabetic agents other than metformin within 2 months prior to Screening (for Schedule A)/Pre-Screening (for Schedule B).
• Has body mass index within 23kg/m2 and 45kg/m2 unless the subject is Asian or of Asian descent, for whom the allowable body mass index will be ≥20 kg/m2 and ≤35 kg/m2, inclusive.
• Has fasting C-peptide concentration at least 0.8 ng.
• If regularly using non-excluded medications, must be on a stable dose at least 4 wks prior to Screening/Pre-screening.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant, lactating or intends to donate ova from Screening throughout the duration of the study.
• Must be able and willing to monitor their blood glucose concentrations with a home monitor, and comply with protocol requirements including scheduled clinic appointments.

Exclusion Criteria:

• Systolic blood pressure greater than or equal to 150 mmHg and/or diastolic pressure greater than or equal to 90.
• Hemoglobin less than or equal to 12 g/dL for males and less than or equal to 10 g/dL for females at Screening Visit.
• Alanine aminotransferase greater than or equal to 2.5 times the upper limit of normal at Screening Visit.
• Serum creatinine greater than or equal to 1.5 mg/dL for males and 1.4 for females, or calculated creatinine clearance less than 60 L/min.
• Males intending to impregnate others or donate sperm before, during or within 1 month after participating in the study.
• A history of cancer other than squamous or basal cell carcinoma of the skin that has not been in full remission for at least 5 yrs.
• A history of laser treatment for diabetic retinopathy within 6 months of screening.
• Treated for diabetic gastric paresis, gastric banding, or gastric bypass.
• New York Heart Association Class III or IV heart failure.
• History of coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, stroke or transient ischemic attack within 3 months prior to screening.
• Known history of human immunodeficiency virus, hepatitis B or C.
• Alcohol or substance abuse within 2 years prior to screening.

• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

  • Any investigational drug within 30 days
  • Any investigational diabetic drug within 3 months
  • Any antidiabetic drug in the dipeptidyl peptidase-4 inhibitors or glucagon-like peptide-1 mimetics classes within 90 days prior to Screening other than metformin
  • Prior treatment with alogliptin.
  • Weight-loss drugs
  • Investigational antidiabetics
  • Oral or systemically injected glucocorticoids
• A hypersensitivity allergy or anaphylactic reaction to any dipeptidyl peptidase-4 drug, metformin or glipizide.
• Has a documented history or concurrent signs of significant thyroid disease (eg, autoimmune thyroid diseases such as Graves disease and Hashimoto thyroiditis or active thyroid nodules).