The CANTATA-MP Trial (CANagliflozin Treatment and Trial Analysis - Metformin and Pioglitazone)

• Percentage of Patients With HbA1c <7% at Week 26 [ Time Frame: Week 26 ] [ Designated as safety issue: No ]
  The table below shows the percentage of patients with HbA1c<7% at Week 26 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
• Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
• Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  HOMA2-%B is a measure of beta cell function (the cells in the pancreas that produce and store insulin). The table below shows the least-squares (LS) mean change in HOMA2-%B from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
• Percent Change in Body Weight From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
• Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
• Percent Change in Triglycerides From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  The table below shows the least-squares (LS) mean percent change in triglycerides from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
• Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 [ Time Frame: Day 1 (Baseline) and Week 26 ] [ Designated as safety issue: No ]
  The table below shows the least-squares (LS) mean percent change in HDL-C from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.

• To assess the effect of study drug on change from baseline in HbA1c [ Time Frame: After 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug on change from baseline in fasting plasma glucose (FPG), fasting plasma lipids, and beta-cell function [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug on the proportion of patients achieving an 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 body weight [ Time Frame: After 26 and 52 weeks of treatment ] [ Designated as safety issue: No ]
• To assess the effect of study drug on time to rescue therapy and proportion of patients requiring rescue therapy [ 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 receving treatment with metformin and pioglitazone 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 or the study doctor will know the name of the assigned treatment), parallel-group, 3-arm (3 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) in patients with T2DM who are not achieving an adequate response from current antihyperglycemic therapy with metformin and pioglitazone to control their diabetes. Approximately 360 patients with T2DM who are receiving combination therapy with metformin and pioglitazone will receive the addition of once-daily treatment with canagliflozin (100 mg or 300 mg) or placebo capsules for 26 weeks followed by a 26-week extension period where patients treated with canagliflozin (100 mg or 300 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, an antihyperglycemic agent administered once-daily for 26 weeks. In addition, all patients will take protocol specified stable doses of metformin and pioglitazone along with assigned study drug for the duration of the study. Patients will participate in the study for approximately 59 to 78 weeks. During the study, if a patient's fasting blood sugar remains high despite treatment with study drug, the patient will receive treatment with glimepiride (rescue therapy) in accordance 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 signs measurements, body weight, physical examinations, and self-monitored blood glucose (SMGB) measurements. The primary outcome measure in the study is 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 capsules for 2 weeks before randomization. After randomization, patients will take double-blind canagliflozin (100 mg or 300 mg) for 52 weeks OR placebo for 26 weeks switched to double-blind sitagliptin 100 mg for 26 weeks.

• Drug: Placebo
  One matching placebo capsule orally (by mouth) once daily for 26 weeks with stable doses of metformin and pioglitazone.
• Drug: Canagliflozin
  One 100 mg or 300 mg over-encapsulated tablet orally once daily for 52 weeks with stable doses of metformin and pioglitazone.
• Drug: Sitagliptin
  One 100 mg over-encapsulated tablet orally once daily beginning at Week 26 until Week 52 with stable doses of metformin and pioglitazone.
• Drug: Metformin
  The patient's stable dose of metformin background therapy should be continued throughout the study.
• Drug: Pioglitazone
  The patient's stable dose of pioglitazone background therapy should be continued throughout the study.

• Placebo/Sitagliptin
  Each patient will receive matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients will be switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52.
  Interventions:

  • Drug: Placebo
  • Drug: Sitagliptin
  • Drug: Metformin
  • Drug: Pioglitazone
• Experimental: Canagliflozin 100 mg
  Each patient will receive 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
  Interventions:

  • Drug: Canagliflozin
  • Drug: Metformin
  • Drug: Pioglitazone
• Experimental: Canagliflozin 300 mg
  Each patient will receive 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone.
  Interventions:

  • Drug: Canagliflozin
  • Drug: Metformin
  • Drug: Pioglitazone

Inclusion Criteria:

• All patients must have a diagnosis of T2DM and be currently treated with PPAR gamma agent ((pioglitazone or rosiglitazone) and another anti-diabetes agent (metformin)
• Patients in the study must have a HbA1c between >=7 and <=10.5% and 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, or diabetes secondary to pancreatitis or pancreatectomy
• or a severe hypoglycemic episode within 6 months before screening