• Change from Baseline in glycosylated hemoglobin level. [ Time Frame: Weeks 4, 8, 12, 16 and 20. ] [ Designated as safety issue: No ]
• Change from Baseline in fasting plasma glucose. [ Time Frame: Weeks 1, 2, 4, 8, 12, 16, 20 and 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of marked hyperglycemia (fasting plasma glucose greater than or equal to 200 mg per dL. [ Time Frame: At Each Occurrence ] [ Designated as safety issue: No ]
• Incidence of rescue. [ Time Frame: At Each Occurrence ] [ Designated as safety issue: No ]
• Change from Baseline in fasting proinsulin. [ Time Frame: Weeks 4, 8, 12, 16, 20 and 26 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in insulin. [ Time Frame: Weeks 4, 8, 12, 16, 20, and 26 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in proinsulin to insulin ratio. [ Time Frame: Weeks 4, 8, 12, 16, 20 and 26 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in C-peptide. [ Time Frame: Weeks 4, 8, 12, 16, 20 and 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin less than or equal to 6.5%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin less than or equal to 7.0%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin less than or equal to 7.5%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin decrease from Baseline greater than or equal to 0.5%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin decrease from Baseline greater than or equal to 1.0%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin decrease from Baseline greater than or equal to 1.5%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Incidence of glycosylated hemoglobin decrease from Baseline greater than or equal to 2.0%. [ Time Frame: Week 26 or Final Visit ] [ Designated as safety issue: No ]
• Change from Baseline in body weight [ Time Frame: Weeks 8, 12, 20 and 26 or Final Visit ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate the efficacy and safety of SYR-322 combined with metformin in adults with type 2 diabetes mellitus.

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 for the improvement of glycemic control in patients with type 2 diabetes mellitus. SYR-322 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 effectiveness of SYR-322 in combination with metformin in individually who are inadequately controlled on metformin alone.

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).

• Drug: SYR-322 and metformin
  SYR-322 12.5 mg, tablets, orally, once daily and metformin for up to 26 weeks.
  Other Names:

  • alogliptin
  • SYR110322
  • Glucophage
• Drug: SYR-322 and metformin
  SYR-322 25 mg, tablets, orally, once daily and metformin for up to 26 weeks.
  Other Names:

  • alogliptin
  • SYR110322
  • Glucophage
• Drug: Metformin
  SYR-322 placebo-matching tablets, orally, once daily and metformin for up to 26 weeks.
  Other Name: Glucophage

• 1: Experimental
  Intervention: Drug: SYR-322 and metformin
• 2: Experimental
  Intervention: Drug: SYR-322 and metformin
• 3: Placebo Comparator
  Intervention: Drug: Metformin

Inclusion Criteria

• Diagnosis of type 2 diabetes mellitus currently treated with metformin alone but, experiencing inadequate glycemic control. The subject should have received the metformin monotherapy for at least the 3 months prior to Screening; and must have a stable dose of greater than or equal to 1500 mg metformin for at least 8 weeks prior to randomization. Subjects with a maximum tolerated dose that is documented to be less than 1500 mg of metformin may also be enrolled if this dose has been stable for 8 weeks prior to randomization.
• No treatment with antidiabetic agents other than metformin 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 to 10 g per dL for females
• Alanine aminotransferase less than or equal to 3 time the upper limit of normal
• Serum creatinine less than1.5 mg per dL for males and less than 1.4 mg per dL for females
• 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 SYR-322

• Excluded Medications:

  • Treatment with antidiabetic agents other than study drug or metformin 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 be instructed not to take any medications, including over-the-counter products, without first consulting with the investigator.