CANVAS - CANagliflozin cardioVascular Assessment Study

Study Overview
=================
Brief Summary
-----------------
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 (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin. The data from this study will be combined with the data from CANVAS-R study (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT01989754) in a pre-specified integrated analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.

Detailed Description
-----------------
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. 4,330 participants will be randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 1:1:1 ratio. This study was originally designed to last for up to 9 years. As per FDA post-marketing requirements for canagliflozin, the study's last subject last visit will now occur when enough MACE events (ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the CANVAS (this study) and CANVAS-R studies. The completion target was reached in February 2017.

Official Title
-----------------
A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of JNJ-28431754 on Cardiovascular Outcomes in Adult Subjects With Type 2 Diabetes Mellitus

Conditions
-----------------
Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors

Intervention / Treatment
-----------------
* Drug: Placebo
* Drug: Canagliflozin (JNJ-28431754) 100 mg
* Drug: Canagliflozin (JNJ-28431754) 300 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a diagnosis of type 2 diabetes mellitus and greater than or equal to (>=) 30 yrs old with history of cardiovascular (CV) event, or >= 50 yrs old with high risk of CV events 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

Ages Eligible for Study
-----------------
Minimum Age: 30 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Each patient will receive placebo (inactive medication) on background standard of care for diabetes once daily for the duration of the study | Drug: Placebo<br>* One placebo capsule taken orally (by mouth) once daily<br>|
| Experimental: Canagliflozin (JNJ-28431754) 100 mg<br>Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily on background standard of care for diabetes once daily for the duration of the study | Drug: Canagliflozin (JNJ-28431754) 100 mg<br>* One 100 mg capsule taken orally (by mouth) once daily<br>|
| Experimental: Canagliflozin (JNJ-28431754) 300 mg<br>Each patient will receive canagliflozin (JNJ-28431754) 300 mg once daily on background standard of care for diabetes once daily for the duration of the study | Drug: Canagliflozin (JNJ-28431754) 300 mg<br>* One 300 mg capsule taken orally (by mouth) once daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | MACE, defined as a composite of CV death, non-fatal MI, and nonfatal stroke. Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of MACE are presented. | Up to approximately 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) | The homeostatic model assessment (HOMA) quantifies insulin resistance and beta-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady-state beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100 percent. | Baseline and end of treatment (approximately 338 weeks) | 
| Percentage of Participants With Progression of Albuminuria at the End-of-Treatment | Progression defined as the development of micro-albuminuria (albumin/creatinine ratio (ACR) greater than or equal to [>=] 30 milligram per gram (mg/g) and less than or equal to <= 300 mg/g) or macroalbuminuria (ACR of >300 mg/g) in a participant with baseline normoalbuminuria or the development of macro-albuminuria in a participant with baseline microalbuminuria. Percentage of participants with progression of albuminuria at the end-of-treatment were assessed. | End of treatment (approximately 338 weeks) | 
| Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment | A raised proinsulin-to-insulin ratio due to impaired processing of proinsulin is an early marker of beta cell dysfunction. Beta-cell dysfunction was evaluated by calculating the PI/I ratio, which estimates the capacity of beta cells to convert proinsulin to insulin and may represent an acceptable method to indicate the degree of beta-cell secretion. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment | Urinary Albumin/Creatinine Ratio is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine. | Baseline and End of treatment (approximately 338 weeks) | 
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment | Change from baseline in Estimated Glomerular Filtration Rate (eGFR) was assessed at end of treatment. GFR is a measure of the rate at which blood is filtered by the kidney. Modification of Diet in Renal Disease (MDRD) is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and sex. eGFR milliliters/minute/1.73 meters square (mL/min/1.73 m^2) = 175 * (serum creatinine) ^ 1.154 * (Age) ^-0.203 *(0.742 if female) * (1.21 if Black). | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment | Change from baseline in glycated hemoglobin (HbA1c) percentage (%) was assessed at end of treatment. Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the average glucose concentration in the blood. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment | Change from baseline in the fasting plasma glucose levels at end-of-treatment was assessed. | Baseline and end of treatment (approximately 338 weeks) | 
| Percent Change From Baseline in Body Weight at End-of-Treatment | Percent change from baseline in body weight was assessed at the end of treatment. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | Change from baseline in systolic blood pressure and diastolic blood pressure was assessed. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Triglycerides Levels at End-of-Treatment | Change from baseline in triglycerides levels was assessed. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | Change from baseline in cholesterol, high-density lipoprotein cholesterol and low density lipoprotein cholesterol levels were assessed. | Baseline and end of treatment (approximately 338 weeks) | 
| Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment | Change from baseline in LDL-C to HDL-C ratio was assessed. | Baseline and end of treatment (approximately 338 weeks) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetes, Type 2 diabetes mellitus, Cardiovascular risk, Cardiovascular outcomes, Canagliflozin (JNJ-28431754), Placebo