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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

Tracking Information
First Submitted Date  ICMJE February 17, 2014
First Posted Date  ICMJE February 19, 2014
Results First Submitted Date  ICMJE October 30, 2019
Results First Posted Date  ICMJE November 20, 2019
Last Update Posted Date December 5, 2019
Actual Study Start Date  ICMJE February 17, 2014
Actual Primary Completion Date October 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: February 17, 2014)
Time to the First Occurrence of an Event in the Primary Composite Endpoint [ Time Frame: Baseline, up to Month 66 ]
The primary composite endpoint of the study includes end-stage kidney disease (ESKD), doubling of serum creatinine, renal or cardiovascular (CV) death.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 30, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2014)
  • Time to the First Occurrence of an Event in the CV Composite Endpoint [ Time Frame: Baseline, up to Month 66 ]
    The CV composite endpoint includes CV death, non-fatal myocardial infarction (MI), non- fatal stroke, hospitalized congestive heart failure and hospitalized unstable angina.
  • Time to the First Occurrence of an Event in the Renal Composite Endpoint [ Time Frame: Baseline, up to Month 66 ]
    The renal composite endpoint includes ESKD, doubling of serum creatinine, and renal death.
  • Time to All-cause Death [ Time Frame: Baseline, up to Month 66 ]
    All deaths occurring during the study from any cause.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy
Official Title  ICMJE 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
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).
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Diabetes Mellitus, Type 2
  • Diabetic Nephropathy
Intervention  ICMJE
  • Drug: Canagliflozin
    One 100 mg over-encapsulated tablet orally once daily
  • Drug: Placebo
    One matching placebo capsule orally (by mouth) once daily
Study Arms  ICMJE
  • Experimental: Canagliflozin 100 mg
    Each participant will receive 100 mg of canagliflozin once daily
    Intervention: Drug: Canagliflozin
  • Placebo Comparator: Placebo
    Each participant will receive matching placebo once daily
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 9, 2019)
4401
Original Estimated Enrollment  ICMJE
 (submitted: February 17, 2014)
3627
Actual Study Completion Date  ICMJE October 30, 2018
Actual Primary Completion Date October 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Brazil,   Bulgaria,   Canada,   Chile,   China,   Colombia,   Czechia,   France,   Germany,   Guatemala,   Hungary,   India,   Japan,   Korea, Republic of,   Lithuania,   Malaysia,   Mexico,   New Zealand,   Philippines,   Poland,   Puerto Rico,   Romania,   Russian Federation,   Serbia,   Slovakia,   South Africa,   Spain,   Taiwan,   Ukraine,   United Arab Emirates,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Egypt,   Hong Kong
 
Administrative Information
NCT Number  ICMJE NCT02065791
Other Study ID Numbers  ICMJE CR103517
2013-004494-28 ( EudraCT Number )
28431754DNE3001 ( Other Identifier: Janssen Research & Development, LLC )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Janssen Research & Development, LLC
Study Sponsor  ICMJE Janssen Research & Development, LLC
Collaborators  ICMJE The George Institute for Global Health, Australia
Investigators  ICMJE
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
PRS Account Janssen Research & Development, LLC
Verification Date December 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP