CANVAS - CANagliflozin cardioVascular Assessment Study

• A standard measure of fasting insulin secretion [ Time Frame: Up to end of treatment (approximately 9 years) ] [ Designated as safety issue: No ]
• Progression of albumin in the urine [ Time Frame: Up to end of treatment (approximately 9 years) ] [ Designated as safety issue: Yes ]
• Effectiveness of lowering blood glucose (in substudies of patients who are also taking specific commonly-used diabetes agents) [ Time Frame: Up to Week 18 ] [ Designated as safety issue: No ]

• a standard measure of fasting insulin secretion [ Time Frame: end of treatment (approximately 4 years) ] [ Designated as safety issue: No ]
• progression of albumin in the urine [ Time Frame: end of treatment (approximately 4 years) ] [ Designated as safety issue: Yes ]
• effectiveness of lowering blood glucose (in substudies of patients who are also taking specific commonly-used diabetes agents) [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]

The study will assess canagliflozin (JNJ-28431754) in the treatment of patients with type 2 diabetes mellitus (T2DM) with regard to cardiovascular (CV) risk for major adverse cardiac events. Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin.

The study will evaluate canagliflozin compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM, whose diabetes is not well controlled at the beginning of the study and who have a history of CV events or have a high risk for CV events. The study includes 3 substudies which will compare the effectiveness of lowering blood glucose and assess the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. The patients will receive capsules of canagliflozin (either 100 or 300 mg), or matching placebo, taken by mouth, with study duration for individual patients of up to 9 years.

• Diabetes Mellitus, Type 2
• Cardiovascular Diseases
• Risk Factors

• Drug: Canagliflozin (JNJ-28431754)
  One 100 mg or 300 mg capsule taken orally (by mouth) once daily for up to 9 years
• Drug: Placebo
  One placebo capsule taken orally (by mouth) once daily for up to 9 years

• Placebo Comparator: Placebo
  Each patient will receive placebo (inactive medication) on background standard of care for diabetes once daily for up to 9 years
  Intervention: Drug: Placebo
• Experimental: Canagliflozin (JNJ-28431754) 100 mg
  Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily on background standard of care for diabetes for up to 9 years
  Intervention: Drug: Canagliflozin (JNJ-28431754)
• Experimental: Canagliflozin (JNJ-28431754) 300 mg
  Each patient will receive canagliflozin (JNJ-28431754) 300 mg once daily on background standard of care for diabetes for up to 9 years
  Intervention: Drug: Canagliflozin (JNJ-28431754)

Inclusion Criteria:

• Patients must have a diagnosis of type 2 diabetes mellitus and a history of, or a high risk for, cardiovascular disease
• Patients must have inadequate diabetes control (as defined by glycosylated hemoglobin greater than or equal to 7.0% to less than or equal to 10.5% at screening) and be either (1) not currently on diabetes drug therapy or (2) on therapy with any approved class of diabetes drugs

Exclusion Criteria:

• A history of diabetic ketoacidosis, type 1 diabetes mellitus, pancreas or beta-cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy
• History of one or more severe hypoglycemic (ie, very low blood sugar) episode within 6 months before screening