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

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of canagliflozin compared to placebo on progression of albuminuria in participants with Type 2 Diabetes Mellitus receiving standard care but with inadequate glycemic control and at elevated risk of cardiovascular events.

Detailed Description
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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.

Official Title
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A Randomized, Multicenter, Double-Blind, Parallel, Placebo-Controlled Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects With Type 2 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 2, Albuminuria

Intervention / Treatment
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* Drug: Placebo
* Drug: Canagliflozin, 100 mg
* Drug: Canagliflozin, 300 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Canagliflozin (JNJ-28431754)<br>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. | Drug: Canagliflozin, 100 mg<br>* One 100 mg capsule taken orally (by mouth) once daily<br>Drug: Canagliflozin, 300 mg<br>* One 300 mg capsule taken orally (by mouth) once daily<br>|
| Placebo Comparator: Placebo<br>Each patient will receive placebo (inactive medication) once daily. | Drug: Placebo<br>* One placebo capsule taken orally (by mouth) once daily for 156 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of Albuminuria | Progression defined as the development of micro-albuminuria (Urine Albumin Creatinine Ratio [UACR] 30 to 300 milligram per gram [mg/g]) or macroalbuminuria (Albumin/creatinine ratio [ACR] of greater than [>] 300 mg/g) in a participant with baseline normoalbuminuria (ACR less than [<] 30 mg/g) or the development of macro-albuminuria in a participant with baseline microalbuminuria with an ACR increase greater than or equal to (>=) 30 percent from baseline. Participants with macroalbuminuria at baseline (ACR>300 mg/g) were excluded from the analysis. Event rate was estimated based on the time to the first occurrence of the event. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure | Analyses were using adjudicated events, that is (i.e.) CV death events or hospitalization due to heart failure, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event. | Approximately 3 years | 
| Cardiovascular (CV) Death | Analyses were using adjudicated events, i.e. CV death events, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event. | Approximately 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular outcomes, Type 2 Diabetes Mellitus, T2DM, JNJ-28431754, Antihyperglycemic Agent, Albuminuria, Canagliflozin