Efficacy and Safety of Alogliptin Plus Metformin Compared to Glipizide Plus Metformin in Patients With Type 2 Diabetes Mellitus

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
compared to glipizide in type 2 diabetes mellitus patients whose blood sugar level is
inadequately controlled with metformin therapy.

The duration of this study will be approximately 2 years.

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 23 kg/m^2 and 45 kg/m^2 unless the patient is Asian or of
Asian descent, for whom the allowable body mass index will be ≥ 20 kg/m^2 and ≤ 35
kg/m^2, 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 weeks
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 years.

- 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

- 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).