The CANTATA-D Trial (CANagliflozin Treatment and Trial Analysis - DPP-4 Inhibitor Comparator Trial)

• To assess the effect of postprandial plasma glucose concentrations [ Time Frame: After 26 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug on the proportion of patients achieving HbA1c <7% and <6.5% [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug on systolic and diastolic blood pressure and fasting plasma lipids [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug HbA1c [ Time Frame: After 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effects of study drug on fasting plasma glucose (FPG) and body weight [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]

• Effect of study drug HbA1c [ Time Frame: After 52 weeks of treatment ] [ Designated as safety issue: No ]
• Effects of study drug on fasting plasma glucose (FPG) and body weight [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• Effect of postprandial plasma glucose concentrations [ Time Frame: After 26 weeks of treatment ] [ Designated as safety issue: No ]
• Effect of study drug on the proportion of patients achieving HbA1c <7% and <6.5% [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• Effect of study drug on systolic and diastolic blood pressure and fasting plasma lipids [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]

The purpose of this study is to evaluate the efficacy and safety of 2 different doses of canagliflozin compared with placebo in patients with type 2 diabetes mellitus who are receiving treatment with metformin monotherapy (i.e., treatment with a single drug) and have inadequate glycemic (blood sugar) control.

Canagliflozin is a drug that is being tested to see if it may be useful in treating patients diagnosed with type 2 diabetes mellitus (T2DM). This is a randomized (study drug assigned by chance), double-blind (neither the patient nor the study doctor will know the identity of assigned study drug), placebo- and active-controlled, parallel-group, 4-arm (4 treatment groups) multicenter study to determine the efficacy, safety, and tolerability of canagliflozin (100 mg and 300 mg) compared to placebo (a capsule that looks like all the other treatments but has no real medicine) and an active-control (sitagliptin 100 mg, an antihyperglycemic agent) in patients with T2DM who are not achieving an adequate response from current antihyperglycemic therapy with metformin Immediate Release (IR) to control their diabetes. Approximately 1,260 patients with T2DM who are receiving treatment with metformin IR and have inadequate glycemic (blood sugar) will receive once-daily treatment with canagliflozin (100 mg or 300 mg), sitagliptin 100 mg, or placebo capsules for 26 weeks (Period I) followed by another 26-weeks where patients treated with canagliflozin (100 mg or 300 mg) or sitagliptin 100 mg will continue treatment for an additional 26 weeks and patients treated with placebo will be switched to active double-blind treatment with sitagliptin 100 mg capsules administered once-daily for 26 weeks (Period II). In addition, all patients will take protocol specified stable doses of metformin IR along with assigned study drug for the duration of the study. Patients will participate in the study for approximately 59 to 71 weeks. During the study, if a patient's fasting blood sugar remains high despite treatment with study drug, metformin IR, and reinforcement with diet and exercise, the patient will receive treatment with glimepiride (rescue therapy) consistent with local prescribing information. During treatment, patients will be monitored for safety by review of adverse events, results from laboratory tests, 12-lead electrocardiograms (ECGs), vital sign measurements, body weight, physical examinations, and self-monitored blood glucose (SMGB) measurements. The primary outcome measure in the study is to assess the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c) after 26 weeks of treatment. Study drug will be taken orally (by mouth) once daily before the first meal each day unless otherwise specified. Patients will take single-blind placebo for 2 weeks before randomization. After randomization, patients in the study will take double-blind canagliflozin (100 mg or 300 mg) or sitagliptin 100 mg for 52 weeks OR placebo for 26 weeks switched to double-blind treatment with sitaliptin 100 mg for 26 weeks.

• Drug: Placebo
  1 placebo capsule once daily for 26 weeks
• Drug: Canagliflozin 100 mg
  100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
• Drug: Sitagliptin 100 mg
  100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
• Drug: Canagliflozin 300 mg
  300 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
• Drug: Sitagliptin 100 mg
  Sitagliptin 100 mg capsule once daily beginning at Week 26 for 26 weeks with protocol-specified doses of Metformin IR
• Drug: Metformin IR
  The patient's stable dose of background Metformin IR therapy should be continued throughout the study.

• Experimental: Canagliflozin 100 mg
  Canagliflozin 100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
  Interventions:

  • Drug: Canagliflozin 100 mg
  • Drug: Metformin IR
• Experimental: Canagliflozin 300 mg
  Canagliflozin 300 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
  Interventions:

  • Drug: Canagliflozin 300 mg
  • Drug: Metformin IR
• Active Comparator: Sitigliptin 100 mg
  Sitagliptin 100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin IR.
  Interventions:

  • Drug: Sitagliptin 100 mg
  • Drug: Metformin IR
• Placebo Crossover to Sitagliptin
  Placebo/ sitagliptin 100 mg 1 placebo capsule once daily for 26 weeks then crossover to 1 sitaliptin 100 mg capsule once daily beginning at Week 26 for 26 weeks with protocol-specified doses of Metformin IR.
  Interventions:

  • Drug: Placebo
  • Drug: Sitagliptin 100 mg
  • Drug: Metformin IR

Inclusion Criteria:

• All patients must have a diagnosis of T2DM and be currently treated with metformin IR
• Patients in the study must have a HbA1c between >=7 and <=10.5%
• Patients must have a fasting plasma glucose (FPG) <270 mg/dL (15 mmol/L)

Exclusion Criteria:

• History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta cell transplantation, diabetes secondary to pancreatitis or pancreatectomy, or a severe hypoglycemic episode within 6 months before screening