Diabetes Mellitus, Type 2, Diabetic Nephropathy
Conditions
Keywords
Diabetes Mellitus, Type 2, Diabetic Nephropathies, Canagliflozin, JNJ-28431754, End-Stage Kidney Disease, Chronic Kidney Disease, Macroalbuminuria
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.
Interventions
DRUGCanagliflozin
One 100 mg over-encapsulated tablet orally once daily
DRUGPlacebo
One matching placebo capsule orally (by mouth) once daily
Sponsors
The George Institute for Global Health, Australia
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Composite Endpoint of Doubling of Serum Creatinine (DoSC), End-stage Kidney Disease (ESKD), and Renal or Cardiovascular (CV) Death | 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
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiac Event (MACE) | 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) | 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 | 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. |
| Composite Endpoint of CV Death and Hospitalized Heart Failure (HHF) | 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. |
| All-cause Mortality | 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 | 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. |
| Cardiovascular (CV) Death | 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. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czechia, France, Germany, Guatemala, Hungary, India, Japan, Lithuania, Malaysia, Mexico, New Zealand, Philippines, Poland, Puerto Rico, Romania, Russia, Serbia, Slovakia, South Africa, South Korea, Spain, Taiwan, Ukraine, United Arab Emirates, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 12900 participants were pre-screened, of those, 8932 were screened. A total of 4401 participants were randomized, with 2199 and 2202 participants assigned to placebo and canagliflozin 100 milligrams (mg), respectively.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received matching placebo orally once daily. | 2,199 |
| Canagliflozin 100 mg Participants received canagliflozin 100 milligram (mg) orally once daily. | 2,202 |
| Total | 4,401 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Closed Site | 1 | 1 |
| Overall Study | Lost to Follow-up | 13 | 9 |
| Overall Study | Withdrawal by Subject | 11 | 5 |
Baseline characteristics
| Characteristic | Placebo | Total | Canagliflozin 100 mg |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 9.23 | 63 years STANDARD_DEVIATION 9.2 | 62.9 years STANDARD_DEVIATION 9.17 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 706 Participants | 1423 Participants | 717 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1457 Participants | 2893 Participants | 1436 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 36 Participants | 85 Participants | 49 Participants |
| Race/Ethnicity, Customized Asian | 452 Participants | 877 Participants | 425 Participants |
| Race/Ethnicity, Customized Black or African American | 112 Participants | 224 Participants | 112 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 554 Participants | 1121 Participants | 567 Participants |
| Race/Ethnicity, Customized Other | 199 Participants | 388 Participants | 189 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 882 Participants | 1791 Participants | 909 Participants |
| Region of Enrollment ARGENTINA | 205 Participants | 426 Participants | 221 Participants |
| Region of Enrollment AUSTRALIA | 18 Participants | 38 Participants | 20 Participants |
| Region of Enrollment BRAZIL | 162 Participants | 314 Participants | 152 Participants |
| Region of Enrollment BULGARIA | 13 Participants | 29 Participants | 16 Participants |
| Region of Enrollment CANADA | 93 Participants | 172 Participants | 79 Participants |
| Region of Enrollment CHILE | 30 Participants | 52 Participants | 22 Participants |
| Region of Enrollment CHINA | 63 Participants | 129 Participants | 66 Participants |
| Region of Enrollment COLOMBIA | 42 Participants | 94 Participants | 52 Participants |
| Region of Enrollment CZECH REPUBLIC | 26 Participants | 57 Participants | 31 Participants |
| Region of Enrollment FRANCE | 33 Participants | 61 Participants | 28 Participants |
| Region of Enrollment GERMANY | 6 Participants | 11 Participants | 5 Participants |
| Region of Enrollment GUATEMALA | 26 Participants | 55 Participants | 29 Participants |
| Region of Enrollment HUNGARY | 68 Participants | 135 Participants | 67 Participants |
| Region of Enrollment INDIA | 82 Participants | 144 Participants | 62 Participants |
| Region of Enrollment ITALY | 39 Participants | 90 Participants | 51 Participants |
| Region of Enrollment JAPAN | 53 Participants | 110 Participants | 57 Participants |
| Region of Enrollment LITHUANIA | 3 Participants | 7 Participants | 4 Participants |
| Region of Enrollment MALAYSIA | 72 Participants | 135 Participants | 63 Participants |
| Region of Enrollment MEXICO | 152 Participants | 303 Participants | 151 Participants |
| Region of Enrollment NEW ZEALAND | 30 Participants | 61 Participants | 31 Participants |
| Region of Enrollment PHILIPPINES | 35 Participants | 71 Participants | 36 Participants |
| Region of Enrollment POLAND | 27 Participants | 50 Participants | 23 Participants |
| Region of Enrollment ROMANIA | 27 Participants | 59 Participants | 32 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 76 Participants | 133 Participants | 57 Participants |
| Region of Enrollment SERBIA | 19 Participants | 40 Participants | 21 Participants |
| Region of Enrollment SLOVAKIA | 32 Participants | 66 Participants | 34 Participants |
| Region of Enrollment SOUTH AFRICA | 34 Participants | 62 Participants | 28 Participants |
| Region of Enrollment SOUTH KOREA | 58 Participants | 122 Participants | 64 Participants |
| Region of Enrollment SPAIN | 58 Participants | 141 Participants | 83 Participants |
| Region of Enrollment TAIWAN | 22 Participants | 37 Participants | 15 Participants |
| Region of Enrollment UKRAINE | 173 Participants | 371 Participants | 198 Participants |
| Region of Enrollment UNITED ARAB EMIRATES | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment UNITED KINGDOM | 59 Participants | 118 Participants | 59 Participants |
| Region of Enrollment UNITED STATES | 363 Participants | 707 Participants | 344 Participants |
| Sex: Female, Male Female | 732 Participants | 1494 Participants | 762 Participants |
| Sex: Female, Male Male | 1467 Participants | 2907 Participants | 1440 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 193 / 2,197 | 164 / 2,200 |
| other Total, other adverse events | 1,447 / 2,197 | 1,320 / 2,200 |
| serious Total, serious adverse events | 806 / 2,197 | 737 / 2,200 |
Outcome results
Primary
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
Population: The Intent-to-treat (ITT) population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Primary Composite Endpoint of Doubling of Serum Creatinine (DoSC), End-stage Kidney Disease (ESKD), and Renal or Cardiovascular (CV) Death | 61.24 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Primary Composite Endpoint of Doubling of Serum Creatinine (DoSC), End-stage Kidney Disease (ESKD), and Renal or Cardiovascular (CV) Death | 43.21 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: <0.000195% CI: [0.59, 0.82]Cox Proportional Hazard
Secondary
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
Population: The ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | All-cause Mortality | 35.00 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | All-cause Mortality | 29.04 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.072795% CI: [0.68, 1.02]Cox proportional hazard
Secondary
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
Population: The ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cardiovascular (CV) Death | 24.38 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Cardiovascular (CV) Death | 19.01 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.050295% CI: [0.61, 1]Cox proportional hazards
Secondary
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
Population: The ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite Endpoint of CV Death and Hospitalized Heart Failure (HHF) | 45.44 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Composite Endpoint of CV Death and Hospitalized Heart Failure (HHF) | 31.47 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.000195% CI: [0.57, 0.83]Cox proportional hazard
Secondary
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
Population: The ITT population consisted of all randomized participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | CV Composite Endpoint | 66.95 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | CV Composite Endpoint | 49.35 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: 0.000195% CI: [0.63, 0.86]Cox proportional hazards
Secondary
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
Population: The ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hospitalized Heart Failure (HHF) | 25.33 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Hospitalized Heart Failure (HHF) | 15.65 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.000395% CI: [0.47, 0.8]Cox proportional hazards
Secondary
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
Population: The ITT population consisted of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Major Adverse Cardiac Event (MACE) | 48.67 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Major Adverse Cardiac Event (MACE) | 38.71 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.012195% CI: [0.67, 0.95]Cox proportional hazard
Secondary
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
Population: The ITT population consisted of all randomized participant.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Renal Composite Endpoint | 40.36 Event rate per 1000 participant-years |
| Canagliflozin 100 mg | Renal Composite Endpoint | 26.99 Event rate per 1000 participant-years |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: <0.000195% CI: [0.53, 0.81]Cox proportional hazards