A Study of the Effects of Canagliflozin (JNJ-28431754) on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus (CANVAS-R)

• Composite Endpoint of Death From Cardiovascular (CV) Causes or Hospitalization for Heart Failure [ Time Frame: Baseline, time to event up to end of study (approximately 3 years) ]
• Death from CV Causes [ Time Frame: Baseline, time to event up to end of study (approximately 3 years) ]

• Number of participants with regression of albuminuria [ Time Frame: Baseline, Week 26, 52, 78, 104, 156 ]
  Regression of albuminuria is defined as the development of normoalbuminuria in a participant with baseline microalbuminuria or macroalbuminuria, or the development of microalbuminuria in a participant with baseline macroalbuminuria, accompanied by a decrease in the urinary ACR value of greater than or equal to 30% from baseline.
• Change in estimated glomerular filtration rate (eGFR) from baseline to the last off-treatment measurement [ Time Frame: Baseline, up to Day 30 of post treatment follow-up ]
• Urinary albumin/creatinine ratio at last on-treatment visit [ Time Frame: Baseline, Week 156 ]

The study will be conducted in adult participants with Type 2 Diabetes Mellitus (T2DM), receiving standard of care for hyperglycemia and cardiovascular (CV) risk factors, who have either a history of a prior CV event or 2 or more risk factors for a CV event. Participants will be randomly assigned in a 1:1 ratio to canagliflozin or matching placebo to be taken once daily. Canagliflozin will be provided at a dose of 100 mg/day through Week 13 and then increased at the discretion of the investigator to a dose of 300 mg/day, if the participant requires additional glycemic control and is tolerating the 100 mg dose.

The study consists of a 2-week screening period and a double-blind treatment period lasting between 78 and 156 weeks; study completion is targeted for when the last subject randomized has approximately 78 weeks of follow-up or when 688 major adverse cardiovascular events are accumulated between CANVAS and CANVAS-R. A total of 5,700 participants are targeted to be recruited into the study. Participants can be either drug naïve to antihyperglycemic agents, using monotherapy, or using combination of antihyperglycemic therapy for the control of blood glucose levels.

The completion target was reached in February 2017.

• Diabetes Mellitus, Type 2
• Albuminuria

• Drug: Placebo
  One placebo capsule taken orally (by mouth) once daily for 156 weeks
• Drug: Canagliflozin, 100 mg
  One 100 mg capsule taken orally (by mouth) once daily
• Drug: Canagliflozin, 300 mg
  One 300 mg capsule taken orally (by mouth) once daily

• Experimental: Canagliflozin (JNJ-28431754)
  Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily during the first 13 weeks, then the dose may be increased to 300 mg once daily.
  Interventions:

  • Drug: Canagliflozin, 100 mg
  • Drug: Canagliflozin, 300 mg
• Placebo Comparator: Placebo
  Each patient will receive placebo (inactive medication) once daily.
  Intervention: Drug: Placebo

Inclusion Criteria:

• Must have a diagnosis of type 2 diabetes mellitus
• Must have inadequate diabetes control (as defined by glycosylated hemoglobin level >=7.0% to <=10.5% at screening)
• Greater than or equal to (>=) 30 yrs old with history of cardiovascular (CV) event, or >= 50 yrs old with high risk of CV events
• Must be either not on antihyperglycemic agents (AHA) therapy, or on AHA monotherapy, or combination AHA therapy with any approved agent for the control of blood glucose levels.

Exclusion Criteria

• 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 episode within 6 months before screening
• History of hereditary glucose-galactose malabsorption or primary renal glucosuria
• Ongoing, inadequately controlled thyroid disorder
• Renal disease that required treatment with immunosuppressive therapy or a history of chronic dialysis or renal transplant
• Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening.