Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy

Phase 3CompletedNCT02065791

Janssen Research & Development, LLC4,401 enrolled

Overview

The goal of this study is to assess whether canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes mellitus (T2DM), Stage 2 or 3 chronic kidney disease (CKD) and macroalbuminuria, who are receiving standard of care including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB).

This is a randomized (the study medication is assigned by chance), double-blind (neither physician nor participant knows the identity of the assigned treatment), placebo-controlled (an inactive substance that is compared with a medication to test whether the medication has a real effect), parallel-group, multicenter study of the effects of canagliflozin on renal and cardiovascular outcomes in participants with type 2 diabetes mellitus (T2DM) and diabetic nephropathy, who are receiving standard of care including a maximum tolerated daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB). The study will consist of a pretreatment phase (several weeks), and a double-blind treatment phase (up to approximately 66 months). During the pretreatment phase all participants will also receive diet/exercise counseling for lipid and blood pressure management as well as counseling on renal and cardiovascular (CV) risk factor medication. A post-treatment follow-up contact or visit will take place approximately 30 days after the last dose of study drug or the completion of the study. The total duration of the study is estimated to be about 5 to 5.5 years. Approximately 4,200 participants will be randomized in a 1:1 ratio to canagliflozin or matching placebo. Participants randomized to canagliflozin will receive a dose of 100 mg once daily. The overall safety and tolerability of canagliflozin will be evaluated by collecting information on adverse events, laboratory tests, vital signs (pulse, blood pressure), physical examination, and body weight.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

Eligibility

Sex: ALLMin age: 30 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Type 2 diabetes mellitus with a hemoglobin A1c (HbA1c) greater than or equal to (\>=) 6.5 percent (%) and less than or equal to (\<=) 12.0%, with an estimated glomerular filtration rate (eGFR) of \>= 30 milliliter (mL)/minute (min)/1.73meter (m)\^2 and less than (\<) 90 mL/min/1.73 m\^2 * Participants need to be on a stable maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least 4 weeks prior to randomization * Must have a urine albumin to creatinine ratio (UACR) of greater than (\>) 300 milligram (mg)/gram (g) and \<= 5000 mg/g Exclusion Criteria: * History of diabetic ketoacidosis or type 1 diabetes mellitus * History of hereditary glucose-galactose malabsorption or primary renal glucosuria * Renal disease that required treatment with immunosuppressive therapy * Known significant liver disease * Current or history of New York Heart Association (NYHA) Class IV heart failure * Blood potassium level \>5.5 millimole (mmol)/liter (L) during Screening

Locations (575)

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Montgomery, Alabama, United States

Unnamed facility

Tempe, Arizona, United States

Unnamed facility

Tucson, Arizona, United States

Unnamed facility

Little Rock, Arkansas, United States

Unnamed facility

Outcomes

Primary Outcomes

Primary Composite Endpoint of Doubling of Serum Creatinine (DoSC), End-stage Kidney Disease (ESKD), and Renal or Cardiovascular (CV) Death

Primary composite endpoint is the composite of DoSC, ESKD, and renal or CV death. DoSC: from baseline average determination (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). ESKD: as initiation of maintenance dialysis for at least 30 days, or renal transplantation, or an estimated glomerular filtration rate (eGFR) value of less than (\<)15 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). Renal death: death in participants who had reached ESKD, died without initiating renal replacement therapy, and no other cause of death was determined via adjudication. Adjudication of these events by Endpoint Adjudication Committee (EAC) was performed in blinded fashion. Event rate estimated based on time to first occurrence of primary composite endpoint are presented.

Time frame: Up to 4.6 years

Secondary Outcomes

Composite Endpoint of CV Death and Hospitalized Heart Failure (HHF)

The composite endpoint included CV death and HHF. CV death included death due to myocardial infarction (MI), stroke, heart failure, sudden death, death during a CV procedure or as a result of procedure-related complications, or death due to other CV causes. For analytic purposes, undetermined causes of death were considered CV deaths. In determining whether a death event was CV in nature, the EAC took into consideration both the proximate and underlying causes. Adjudication of these events by the EAC was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of the composite endpoint of CV death and HHF are presented.

Time frame: Up to 4.6 years

Major Adverse Cardiac Event (MACE)

The composite endpoint included CV death, non-fatal MI, and non-fatal stroke (that is, 3-point MACE). Adjudication of these events by the EAC was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of MACE are presented.

Time frame: Up to 4.6 years

Hospitalized Heart Failure (HHF)

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 hospitalized heart failure are presented.

Time frame: Up to 4.6 years

Renal Composite Endpoint

The renal composite endpoint included composite of DoSC, ESKD and Renal death. DoSC: from the baseline average determination (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). ESKD: initiation of maintenance dialysis for at least 30 days, or renal transplantation, or an eGFR value of \<15 mL/min/1.73 m\^2 (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). Renal death: death in participants who have reached ESKD, died without initiating renal replacement therapy, and no other cause of death was determined via adjudication. Adjudication of these events by the EAC was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of the renal composite endpoint are presented.

Time frame: Up to 4.6 years

Cardiovascular (CV) Death

CV death included death due to MI, stroke, heart failure, sudden death, death during a CV procedure or as a result of procedure-related complications, or death due to other CV causes. For analytic purposes, undetermined causes of death were considered CV deaths. In determining whether a death event was a CV in nature, the EAC took into consideration both the proximate and underlying causes. Adjudication of these events by the EAC was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of CV death are presented.

Time frame: Up to 4.6 years

All-cause Mortality

Adjudication of these events by Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. Event rate estimated based on time to first occurrence of all-cause mortality are presented.

Time frame: Up to 4.6 years

CV Composite Endpoint

The CV composite endpoint included the CV death, non-fatal MI, non-fatal stroke, hospitalized heart failure, and hospitalized unstable angina. CV death included death due to MI, stroke, heart failure, sudden death, death during a CV procedure or as a result of procedure-related complications, or death due to other CV causes. For analytic purposes, undetermined causes of death were considered CV deaths. In determining whether a death event was a CV in nature, the EAC took into consideration both the proximate and underlying causes. Adjudication of these events by the EAC was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of the CV composite endpoint are presented.

Time frame: Up to 4.6 years

Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy

Overview

Conditions

Interventions

Eligibility

Locations (575)

Outcomes

Primary Outcomes

Secondary Outcomes