Cardiovascular Diseases, Diabetes Mellitus, Type 2, Risk Factors
Conditions
Keywords
Diabetes, Type 2 diabetes mellitus, Cardiovascular risk, Cardiovascular outcomes, Canagliflozin (JNJ-28431754), Placebo
Brief summary
The study will assess canagliflozin (JNJ-28431754) in the treatment of patients with type 2 diabetes mellitus (T2DM) with regard to cardiovascular (CV) risk for major adverse cardiac events (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin. The data from this study will be combined with the data from CANVAS-R study (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT01989754) in a pre-specified integrated analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.
Detailed description
The study will evaluate canagliflozin compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM, whose diabetes is not well controlled at the beginning of the study and who have a history of CV events or have a high risk for CV events. The study includes 3 substudies which will compare the effectiveness of lowering blood glucose and assess the safety of canagliflozin relative to placebo in patients receiving specific commonly-used diabetes agents. 4,330 participants will be randomly assigned to treatment with 1 of 2 doses of canagliflozin (100 or 300 mg) or placebo, in a 1:1:1 ratio. This study was originally designed to last for up to 9 years. As per FDA post-marketing requirements for canagliflozin, the study's last subject last visit will now occur when enough MACE events (ie, CV death, nonfatal myocardial infarction, nonfatal stroke) are accumulated between the CANVAS (this study) and CANVAS-R studies. The completion target was reached in February 2017.
Interventions
DRUGPlacebo
One placebo capsule taken orally (by mouth) once daily
DRUGCanagliflozin (JNJ-28431754) 100 mg
One 100 mg capsule taken orally (by mouth) once daily
One 300 mg capsule taken orally (by mouth) once daily
Sponsors
Janssen Research & Development, LLC
The George Institute for Global Health, Australia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have a diagnosis of type 2 diabetes mellitus and greater than or equal to (\>=) 30 yrs old with history of cardiovascular (CV) event, or \>= 50 yrs old with high risk of CV events * Patients must have inadequate diabetes control (as defined by glycosylated hemoglobin greater than or equal to 7.0% to less than or equal to 10.5% at screening) and be either (1) not currently on diabetes drug therapy or (2) on therapy with any approved class of diabetes drugs
Exclusion criteria
* A 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 (ie, very low blood sugar) episode within 6 months before screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | Up to approximately 8 years | MACE, defined as a composite of CV death, non-fatal MI, and nonfatal stroke. 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 MACE are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) | Baseline and end of treatment (approximately 338 weeks) | The homeostatic model assessment (HOMA) quantifies insulin resistance and beta-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady-state beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100 percent. |
| Percentage of Participants With Progression of Albuminuria at the End-of-Treatment | End of treatment (approximately 338 weeks) | Progression defined as the development of micro-albuminuria (albumin/creatinine ratio (ACR) greater than or equal to \[\>=\] 30 milligram per gram (mg/g) and less than or equal to \<= 300 mg/g) or macroalbuminuria (ACR of \>300 mg/g) in a participant with baseline normoalbuminuria or the development of macro-albuminuria in a participant with baseline microalbuminuria. Percentage of participants with progression of albuminuria at the end-of-treatment were assessed. |
| Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | A raised proinsulin-to-insulin ratio due to impaired processing of proinsulin is an early marker of beta cell dysfunction. Beta-cell dysfunction was evaluated by calculating the PI/I ratio, which estimates the capacity of beta cells to convert proinsulin to insulin and may represent an acceptable method to indicate the degree of beta-cell secretion. |
| Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment | Baseline and End of treatment (approximately 338 weeks) | Urinary Albumin/Creatinine Ratio is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine. |
| Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in Estimated Glomerular Filtration Rate (eGFR) was assessed at end of treatment. GFR is a measure of the rate at which blood is filtered by the kidney. Modification of Diet in Renal Disease (MDRD) is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and sex. eGFR milliliters/minute/1.73 meters square (mL/min/1.73 m\^2) = 175 \* (serum creatinine) \^ 1.154 \* (Age) \^-0.203 \*(0.742 if female) \* (1.21 if Black). |
| Percent Change From Baseline in Body Weight at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Percent change from baseline in body weight was assessed at the end of treatment. |
| Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in the fasting plasma glucose levels at end-of-treatment was assessed. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in systolic blood pressure and diastolic blood pressure was assessed. |
| Change From Baseline in Triglycerides Levels at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in triglycerides levels was assessed. |
| Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in cholesterol, high-density lipoprotein cholesterol and low density lipoprotein cholesterol levels were assessed. |
| Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in LDL-C to HDL-C ratio was assessed. |
| Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment | Baseline and end of treatment (approximately 338 weeks) | Change from baseline in glycated hemoglobin (HbA1c) percentage (%) was assessed at end of treatment. Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the average glucose concentration in the blood. |
Countries
Argentina, Australia, Belgium, Canada, Colombia, Czechia, Estonia, France, Germany, Hungary, India, Israel, Luxembourg, Malaysia, Mexico, Netherlands, New Zealand, Norway, Poland, Russia, Spain, Sweden, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
No Text enterred
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received one placebo capsule orally once daily for the duration of the study or until early discontinuation from treatment. | 1,442 |
| Canagliflozin 100 mg Participants received one canagliflozin 100 milligram (mg) capsule once daily for the duration of the study or until early discontinuation from treatment. | 1,445 |
| Canagliflozin 300 mg Participants received one canagliflozin 300 mg capsule once daily for the duration of the study or until early discontinuation from treatment. | 1,443 |
| Total | 4,330 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Closed Site | 21 | 18 | 16 |
| Overall Study | Lost to Follow-up | 74 | 47 | 37 |
| Overall Study | Withdrawal by Subject | 50 | 36 | 35 |
Baseline characteristics
| Characteristic | Placebo | Canagliflozin 100 mg | Canagliflozin 300 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 7.94 | 62.2 Years STANDARD_DEVIATION 8 | 62.8 Years STANDARD_DEVIATION 8.13 | 62.4 Years STANDARD_DEVIATION 8.02 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 149 Participants | 142 Participants | 125 Participants | 416 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1288 Participants | 1300 Participants | 1317 Participants | 3905 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized Asian | 262 Participants | 270 Participants | 263 Participants | 795 Participants |
| Race/Ethnicity, Customized Black or African American | 35 Participants | 32 Participants | 38 Participants | 105 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 134 Participants | 123 Participants | 106 Participants | 363 Participants |
| Race/Ethnicity, Customized Other | 82 Participants | 86 Participants | 88 Participants | 256 Participants |
| Race/Ethnicity, Customized White Non- Hispanic | 929 Participants | 934 Participants | 948 Participants | 2811 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 262 Participants | 270 Participants | 263 Participants | 795 Participants |
| Race (NIH/OMB) Black or African American | 35 Participants | 32 Participants | 38 Participants | 105 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 8 Participants | 13 Participants | 31 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 67 Participants | 72 Participants | 70 Participants | 209 Participants |
| Race (NIH/OMB) White | 1064 Participants | 1060 Participants | 1055 Participants | 3179 Participants |
| Region of Enrollment Argentina | 57 Participants | 48 Participants | 55 Participants | 160 Participants |
| Region of Enrollment Australia | 57 Participants | 60 Participants | 60 Participants | 177 Participants |
| Region of Enrollment Belgium | 3 Participants | 10 Participants | 8 Participants | 21 Participants |
| Region of Enrollment Canada | 134 Participants | 139 Participants | 123 Participants | 396 Participants |
| Region of Enrollment Colombia | 4 Participants | 1 Participants | 2 Participants | 7 Participants |
| Region of Enrollment Czech Republic | 37 Participants | 37 Participants | 43 Participants | 117 Participants |
| Region of Enrollment Estonia | 19 Participants | 13 Participants | 12 Participants | 44 Participants |
| Region of Enrollment Germany | 47 Participants | 62 Participants | 66 Participants | 175 Participants |
| Region of Enrollment Hungary | 38 Participants | 50 Participants | 37 Participants | 125 Participants |
| Region of Enrollment India | 229 Participants | 232 Participants | 234 Participants | 695 Participants |
| Region of Enrollment Israel | 5 Participants | 11 Participants | 9 Participants | 25 Participants |
| Region of Enrollment Luxembourg | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Malaysia | 32 Participants | 24 Participants | 17 Participants | 73 Participants |
| Region of Enrollment Mexico | 40 Participants | 48 Participants | 36 Participants | 124 Participants |
| Region of Enrollment Netherlands | 70 Participants | 77 Participants | 81 Participants | 228 Participants |
| Region of Enrollment New Zealand | 27 Participants | 22 Participants | 25 Participants | 74 Participants |
| Region of Enrollment Norway | 41 Participants | 33 Participants | 35 Participants | 109 Participants |
| Region of Enrollment Poland | 47 Participants | 54 Participants | 43 Participants | 144 Participants |
| Region of Enrollment Russia | 146 Participants | 118 Participants | 125 Participants | 389 Participants |
| Region of Enrollment Spain | 64 Participants | 74 Participants | 71 Participants | 209 Participants |
| Region of Enrollment Sweden | 23 Participants | 26 Participants | 22 Participants | 71 Participants |
| Region of Enrollment Ukraine | 50 Participants | 39 Participants | 58 Participants | 147 Participants |
| Region of Enrollment United Kingdom | 31 Participants | 29 Participants | 32 Participants | 92 Participants |
| Region of Enrollment United States | 240 Participants | 238 Participants | 249 Participants | 727 Participants |
| Sex: Female, Male Female | 486 Participants | 484 Participants | 499 Participants | 1469 Participants |
| Sex: Female, Male Male | 956 Participants | 961 Participants | 944 Participants | 2861 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 74 / 1,441 | 68 / 1,445 | 66 / 1,441 |
| other Total, other adverse events | 1,137 / 1,441 | 1,146 / 1,445 | 1,167 / 1,441 |
| serious Total, serious adverse events | 584 / 1,441 | 601 / 1,445 | 606 / 1,441 |
Outcome results
Primary
Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke
MACE, defined as a composite of CV death, non-fatal MI, and nonfatal stroke. 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 MACE are presented.
Time frame: Up to approximately 8 years
Population: The primary analysis was based on the intent-to-treat (ITT) analysis set for adjudicated MACE, and included all randomized participants. As per planned analysis, the results were reported separately and combined for both doses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | 30.36 Events per 1000 patient-year |
| Canagliflozin 100 mg | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | 28.41 Events per 1000 patient-year |
| Canagliflozin 300 mg | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | 25.37 Events per 1000 patient-year |
| Canagliflozin (Total) | Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke | 26.89 Events per 1000 patient-year |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.457695% CI: [0.78, 1.12]Cox proportional hazard model
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.046795% CI: [0.68, 1]Cox proportional hazard model
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: 0.11295% CI: [0.75, 1.03]Cox proportional hazard method
Secondary
Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment
Change from baseline in cholesterol, high-density lipoprotein cholesterol and low density lipoprotein cholesterol levels were assessed.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | HDL-C (change at EOT) | -0.01 mmol/L | Standard Error 0.006 |
| Placebo | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | Cholesterol (change at EOT) | -0.07 mmol/L | Standard Error 0.028 |
| Placebo | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | LDL-C (change at EOT) | -0.07 mmol/L | Standard Error 0.022 |
| Canagliflozin 100 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | HDL-C (change at EOT) | 0.04 mmol/L | Standard Error 0.006 |
| Canagliflozin 100 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | Cholesterol (change at EOT) | 0.11 mmol/L | Standard Error 0.027 |
| Canagliflozin 100 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | LDL-C (change at EOT) | 0.04 mmol/L | Standard Error 0.022 |
| Canagliflozin 300 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | Cholesterol (change at EOT) | 0.16 mmol/L | Standard Error 0.028 |
| Canagliflozin 300 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | LDL-C (change at EOT) | 0.10 mmol/L | Standard Error 0.023 |
| Canagliflozin 300 mg | Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment | HDL-C (change at EOT) | 0.05 mmol/L | Standard Error 0.006 |
Comparison: Statistical analysis (Cholesterol) Comparison for canagliflozin versus placebo is reported here.95% CI: [0.105, 0.259]
Comparison: Statistical analysis (Cholesterol) Comparison for canagliflozin versus placebo is reported here.95% CI: [0.152, 0.307]
Comparison: Statistical analysis (HDL-C)95% CI: [0.031, 0.065]
Comparison: Statistical analysis (HDL-C) Comparison for canagliflozin versus placebo is reported here.95% CI: [0.04, 0.075]
Comparison: Statistical analysis (LDL-C) Comparison for canagliflozin versus placebo is reported here.95% CI: [0.046, 0.17]
Comparison: Statistical analysis (LDL-C) Comparison for canagliflozin versus placebo is reported here.95% CI: [0.102, 0.226]
Secondary
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment
Change from baseline in Estimated Glomerular Filtration Rate (eGFR) was assessed at end of treatment. GFR is a measure of the rate at which blood is filtered by the kidney. Modification of Diet in Renal Disease (MDRD) is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and sex. eGFR milliliters/minute/1.73 meters square (mL/min/1.73 m\^2) = 175 \* (serum creatinine) \^ 1.154 \* (Age) \^-0.203 \*(0.742 if female) \* (1.21 if Black).
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who had both baseline and post-baseline eGFR measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment | -5.23 mL/min/1.73 m^2 | Standard Error 0.39 |
| Canagliflozin 100 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment | -3.55 mL/min/1.73 m^2 | Standard Error 0.388 |
| Canagliflozin 300 mg | Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment | -3.98 mL/min/1.73 m^2 | Standard Error 0.392 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.599, 2.755]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.16, 2.328]
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment
Change from baseline in the fasting plasma glucose levels at end-of-treatment was assessed.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and had both baseline and post-baseline fasting plasma glucose measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment | 0.16 Millimoles per liter (mmol/L) | Standard Error 0.076 |
| Canagliflozin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment | -0.42 Millimoles per liter (mmol/L) | Standard Error 0.075 |
| Canagliflozin 300 mg | Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment | -0.57 Millimoles per liter (mmol/L) | Standard Error 0.076 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.794, -0.374]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.945, -0.523]
Secondary
Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment
Change from baseline in glycated hemoglobin (HbA1c) percentage (%) was assessed at end of treatment. Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the average glucose concentration in the blood.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who had both baseline and any post-baseline HbA1C measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment | 0.01 HbA1c (%) | Standard Error 0.032 |
| Canagliflozin 100 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment | -0.26 HbA1c (%) | Standard Error 0.032 |
| Canagliflozin 300 mg | Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment | -0.31 HbA1c (%) | Standard Error 0.032 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.355, -0.177]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.405, -0.227]
Secondary
Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT)
The homeostatic model assessment (HOMA) quantifies insulin resistance and beta-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady-state beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100 percent.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) included subset of participants who were not receiving insulin at baseline and had at least one post-baseline HOMA2-%B measurement on-treatment prior to initiation of insulin.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) | 4.02 Percentage of HOMA2 | Standard Error 1.611 |
| Canagliflozin 100 mg | Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) | 6.82 Percentage of HOMA2 | Standard Error 1.533 |
| Canagliflozin 300 mg | Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) | 8.09 Percentage of HOMA2 | Standard Error 1.587 |
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.2195% CI: [-1.571, 7.154]ANCOVA
Comparison: Comparison for canagliflozin versus placebo is reported here.p-value: =0.07295% CI: [-0.368, 8.504]ANCOVA
Secondary
Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment
Change from baseline in LDL-C to HDL-C ratio was assessed.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment | -0.04 Ratio | Standard Error 0.021 |
| Canagliflozin 100 mg | Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment | -0.02 Ratio | Standard Error 0.021 |
| Canagliflozin 300 mg | Change From Baseline in Low-Density Lipoprotein-Cholesterol (LDL-C) to High-Density Lipoprotein-Cholesterol (HDL-C) Ratio at End-of-Treatment | 0.00 Ratio | Standard Error 0.021 |
95% CI: [-0.04, 0.076]
95% CI: [-0.023, 0.094]
Secondary
Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment
A raised proinsulin-to-insulin ratio due to impaired processing of proinsulin is an early marker of beta cell dysfunction. Beta-cell dysfunction was evaluated by calculating the PI/I ratio, which estimates the capacity of beta cells to convert proinsulin to insulin and may represent an acceptable method to indicate the degree of beta-cell secretion.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set: all randomized participants who received at least 1 dose of study drug. 'N' (number of participants analyzed): number of participants evaluable for this outcome measure, had both baseline and any post-baseline PI/I ratio measurements on-treatment prior to initiation of insulin and didn't receive insulin through baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment | 0.70 Picomole per milli international units | Standard Error 0.15 |
| Canagliflozin 100 mg | Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment | 0.67 Picomole per milli international units | Standard Error 0.14 |
| Canagliflozin 300 mg | Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment | 1.03 Picomole per milli international units | Standard Error 0.142 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.429, 0.374]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.079, 0.731]
Secondary
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment
Change from baseline in systolic blood pressure and diastolic blood pressure was assessed.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure who and had both baseline and post-baseline blood pressure measurements.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | DBP (Change at end of treatment) | -2.88 Millimeter of mercury (mmHg) | Standard Error 0.223 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | SBP(Change at end of treatment) | -1.96 Millimeter of mercury (mmHg) | Standard Error 0.377 |
| Canagliflozin 100 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | SBP(Change at end of treatment) | -4.91 Millimeter of mercury (mmHg) | Standard Error 0.375 |
| Canagliflozin 100 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | DBP (Change at end of treatment) | -3.70 Millimeter of mercury (mmHg) | Standard Error 0.221 |
| Canagliflozin 300 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | SBP(Change at end of treatment) | -6.49 Millimeter of mercury (mmHg) | Standard Error 0.378 |
| Canagliflozin 300 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment | DBP (Change at end of treatment) | -4.51 Millimeter of mercury (mmHg) | Standard Error 0.223 |
Comparison: Statistical analysis (Systolic blood pressure) Comparison for canagliflozin versus placebo is reported here.95% CI: [-3.998, -1.914]
Comparison: Statistical analysis (Systolic blood pressure) Comparison for canagliflozin versus placebo is reported here.95% CI: [-5.579, -3.484]
Comparison: Statistical analysis (Diastolic blood pressure) Comparison for canagliflozin versus placebo is reported here.95% CI: [-1.437, -0.205]
Comparison: Statistical analysis (Diastolic blood pressure) Comparison for canagliflozin versus placebo is reported here.95% CI: [-2.245, -1.007]
Secondary
Change From Baseline in Triglycerides Levels at End-of-Treatment
Change from baseline in triglycerides levels was assessed.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline lipid measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Triglycerides Levels at End-of-Treatment | 0.05 mmol/L | Standard Deviation 1.597 |
| Canagliflozin 100 mg | Change From Baseline in Triglycerides Levels at End-of-Treatment | 0.13 mmol/L | Standard Deviation 1.679 |
| Canagliflozin 300 mg | Change From Baseline in Triglycerides Levels at End-of-Treatment | 0.09 mmol/L | Standard Deviation 1.238 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.04, 0.07]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-0.03, 0.08]
Secondary
Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment
Urinary Albumin/Creatinine Ratio is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine.
Time frame: Baseline and End of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and had both baseline and post-baseline ACR measurements.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment | 29.30 Milligram per gram (mg/g) |
| Canagliflozin 100 mg | Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment | 25.50 Milligram per gram (mg/g) |
| Canagliflozin 300 mg | Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment | 24.47 Milligram per gram (mg/g) |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.8, 0.94]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.77, 0.91]
Secondary
Percentage of Participants With Progression of Albuminuria at the End-of-Treatment
Progression defined as the development of micro-albuminuria (albumin/creatinine ratio (ACR) greater than or equal to \[\>=\] 30 milligram per gram (mg/g) and less than or equal to \<= 300 mg/g) or macroalbuminuria (ACR of \>300 mg/g) in a participant with baseline normoalbuminuria or the development of macro-albuminuria in a participant with baseline microalbuminuria. Percentage of participants with progression of albuminuria at the end-of-treatment were assessed.
Time frame: End of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were treated, had both baseline and post-baseline ACR measurements, and baseline ACR\<=300 mg/g.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Progression of Albuminuria at the End-of-Treatment | 24.0 Percentage of participants |
| Canagliflozin 100 mg | Percentage of Participants With Progression of Albuminuria at the End-of-Treatment | 20.2 Percentage of participants |
| Canagliflozin 300 mg | Percentage of Participants With Progression of Albuminuria at the End-of-Treatment | 18.3 Percentage of participants |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.67, 0.97]Regression, Logistic
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [0.58, 0.85]Regression, Logistic
Secondary
Percent Change From Baseline in Body Weight at End-of-Treatment
Percent change from baseline in body weight was assessed at the end of treatment.
Time frame: Baseline and end of treatment (approximately 338 weeks)
Population: On-treatment analysis set included all randomized participants who received at least 1 dose of study drug. Here 'N' (number of participants analyzed) signifies number of participants who were evaluable for this outcome measure and who had both baseline and post-baseline body weight.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Body Weight at End-of-Treatment | -0.50 Percent change | Standard Error 0.184 |
| Canagliflozin 100 mg | Percent Change From Baseline in Body Weight at End-of-Treatment | -3.47 Percent change | Standard Error 0.183 |
| Canagliflozin 300 mg | Percent Change From Baseline in Body Weight at End-of-Treatment | -4.12 Percent change | Standard Error 0.185 |
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-3.472, -2.454]
Comparison: Comparison for canagliflozin versus placebo is reported here.95% CI: [-4.125, -3.103]