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

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ClinicalTrials.gov Identifier: NCT02065791
Recruitment Status : Completed
First Posted : February 19, 2014
Results First Posted : November 20, 2019
Last Update Posted : December 5, 2019
Sponsor:
Collaborator:
The George Institute for Global Health, Australia
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Description
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Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Diabetic Nephropathy Drug: Canagliflozin Drug: Placebo Phase 3

Detailed Description:

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4401 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Event-driven, Placebo-controlled, Multicenter Study of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Subjects With Type 2 Diabetes Mellitus and Diabetic Nephropathy
Actual Study Start Date : February 17, 2014
Actual Primary Completion Date : October 30, 2018
Actual Study Completion Date : October 30, 2018

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Canagliflozin 100 mg
Each participant will receive 100 mg of canagliflozin once daily
 Drug: Canagliflozin
One 100 mg over-encapsulated tablet orally once daily
Placebo Comparator: Placebo
Each participant will receive matching placebo once daily
 Drug: Placebo
One matching placebo capsule orally (by mouth) once daily


Outcome Measures
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Primary Outcome Measures :
  1. Primary Composite Endpoint of Doubling of Serum Creatinine (DoSC), End-stage Kidney Disease (ESKD), and Renal or Cardiovascular (CV) Death [ Time Frame: Up to 4.6 years ]
    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.


Secondary Outcome Measures :
  1. Composite Endpoint of CV Death and Hospitalized Heart Failure (HHF) [ Time Frame: Up to 4.6 years ]
    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.

  2. Major Adverse Cardiac Event (MACE) [ Time Frame: Up to 4.6 years ]
    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.

  3. Hospitalized Heart Failure (HHF) [ Time Frame: Up to 4.6 years ]
    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.

  4. Renal Composite Endpoint [ Time Frame: Up to 4.6 years ]
    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.

  5. Cardiovascular (CV) Death [ Time Frame: Up to 4.6 years ]
    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.

  6. All-cause Mortality [ Time Frame: Up to 4.6 years ]
    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.

  7. CV Composite Endpoint [ Time Frame: Up to 4.6 years ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   30 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02065791


Locations
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Sponsors and Collaborators
Janssen Research & Development, LLC
The George Institute for Global Health, Australia
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:
Study Protocol  [PDF] September 6, 2017
Statistical Analysis Plan  [PDF] June 1, 2018

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02065791    
Other Study ID Numbers: CR103517
2013-004494-28 ( EudraCT Number )
28431754DNE3001 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: February 19, 2014    Key Record Dates
Results First Posted: November 20, 2019
Last Update Posted: December 5, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Janssen Research & Development, LLC:
Diabetes Mellitus, Type 2
Diabetic Nephropathies
Canagliflozin
JNJ-28431754
 End-Stage Kidney Disease
Chronic Kidney Disease
Macroalbuminuria
Additional relevant MeSH terms:
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Kidney Diseases
Diabetic Nephropathies
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Urologic Diseases
Female Urogenital Diseases
 Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Male Urogenital Diseases
Diabetes Complications
Canagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs