Albuminuria, Diabetes Mellitus, Type 2
Conditions
Keywords
Albuminuria, Canagliflozin, Cardiovascular outcomes, Type 2 Diabetes Mellitus, T2DM, JNJ-28431754, Antihyperglycemic Agent
Brief summary
The purpose of this study is to assess the effect of canagliflozin compared to placebo on progression of albuminuria in participants with Type 2 Diabetes Mellitus receiving standard care but with inadequate glycemic control and at elevated risk of cardiovascular events.
Detailed description
The study will be conducted in adult participants with Type 2 Diabetes Mellitus (T2DM), receiving standard of care for hyperglycemia and cardiovascular (CV) risk factors, who have either a history of a prior CV event or 2 or more risk factors for a CV event. Participants will be randomly assigned in a 1:1 ratio to canagliflozin or matching placebo to be taken once daily. Canagliflozin will be provided at a dose of 100 mg/day through Week 13 and then increased at the discretion of the investigator to a dose of 300 mg/day, if the participant requires additional glycemic control and is tolerating the 100 mg dose. The study consists of a 2-week screening period and a double-blind treatment period lasting between 78 and 156 weeks; study completion is targeted for when the last subject randomized has approximately 78 weeks of follow-up or when 688 major adverse cardiovascular events are accumulated between CANVAS and CANVAS-R. A total of 5,700 participants are targeted to be recruited into the study. Participants can be either drug naïve to antihyperglycemic agents, using monotherapy, or using combination of antihyperglycemic therapy for the control of blood glucose levels. The completion target was reached in February 2017.
Interventions
DRUGPlacebo
One placebo capsule taken orally (by mouth) once daily for 156 weeks
One 100 mg capsule taken orally (by mouth) once daily
One 300 mg capsule taken 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
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Must have a diagnosis of type 2 diabetes mellitus * Must have inadequate diabetes control (as defined by glycosylated hemoglobin level \>=7.0% to \<=10.5% at screening) * Greater than or equal to (\>=) 30 yrs old with history of cardiovascular (CV) event, or \>= 50 yrs old with high risk of CV events * Must be either not on antihyperglycemic agents (AHA) therapy, or on AHA monotherapy, or combination AHA therapy with any approved agent for the control of blood glucose levels.
Exclusion criteria
* 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 episode within 6 months before screening * History of hereditary glucose-galactose malabsorption or primary renal glucosuria * Ongoing, inadequately controlled thyroid disorder * Renal disease that required treatment with immunosuppressive therapy or a history of chronic dialysis or renal transplant * Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression of Albuminuria | Up to 3 years | Progression defined as the development of micro-albuminuria (Urine Albumin Creatinine Ratio \[UACR\] 30 to 300 milligram per gram \[mg/g\]) or macroalbuminuria (Albumin/creatinine ratio \[ACR\] of greater than \[\>\] 300 mg/g) in a participant with baseline normoalbuminuria (ACR less than \[\<\] 30 mg/g) or the development of macro-albuminuria in a participant with baseline microalbuminuria with an ACR increase greater than or equal to (\>=) 30 percent from baseline. Participants with macroalbuminuria at baseline (ACR\>300 mg/g) were excluded from the analysis. Event rate was estimated based on the time to the first occurrence of the event. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure | Approximately 3 years | Analyses were using adjudicated events, that is (i.e.) CV death events or hospitalization due to heart failure, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event. |
| Cardiovascular (CV) Death | Approximately 3 years | Analyses were using adjudicated events, i.e. CV death events, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, China, Czechia, France, Germany, Hungary, Italy, Malaysia, Mexico, Netherlands, New Zealand, Poland, Puerto Rico, Russia, South Korea, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
A total of 5,813 participants were randomized. However, 1 participant was randomized twice and only the first randomization was included in the Intent-to-treat (ITT) analysis set. Thus 2,905 and 2,907 participants were randomly assigned to the placebo and canagliflozin groups in the ITT analysis set, respectively.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Placebo) Participants received one capsule of matching placebo orally once daily for the duration of the study or until early discontinuation from treatment. | 2,905 |
| Canagliflozin (Experimental) Participants received canagliflozin (JNJ-28431754) 100 milligram (mg) once daily during the first 13 weeks, then the dose was increased to 300 mg once daily (if the participant required additional glycemic control, provided the 100-mg dose was well tolerated). | 2,907 |
| Total | 5,812 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Closed Site | 1 | 1 |
| Overall Study | Lost to Follow-up | 28 | 20 |
| Overall Study | Withdrawal by Subject | 10 | 14 |
Baseline characteristics
| Characteristic | Placebo (Placebo) | Total | Canagliflozin (Experimental) |
|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 8.28 | 64 years STANDARD_DEVIATION 8.35 | 63.9 years STANDARD_DEVIATION 8.42 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 586 Participants | 1190 Participants | 604 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2303 Participants | 4593 Participants | 2290 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 29 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 245 Participants | 489 Participants | 244 Participants |
| Race/Ethnicity, Customized Black or African American | 125 Participants | 231 Participants | 106 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 407 Participants | 844 Participants | 437 Participants |
| Race/Ethnicity, Customized Other | 174 Participants | 346 Participants | 172 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 1954 Participants | 3902 Participants | 1948 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 19 Participants | 33 Participants | 14 Participants |
| Race (NIH/OMB) Asian | 245 Participants | 489 Participants | 244 Participants |
| Race (NIH/OMB) Black or African American | 125 Participants | 231 Participants | 106 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 19 Participants | 09 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 09 Participants | 17 Participants | 08 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 125 Participants | 258 Participants | 133 Participants |
| Race (NIH/OMB) White | 2372 Participants | 4765 Participants | 2393 Participants |
| Region of Enrollment ARGENTINA | 146 Participants | 305 Participants | 159 Participants |
| Region of Enrollment AUSTRALIA | 58 Participants | 109 Participants | 51 Participants |
| Region of Enrollment BELGIUM | 86 Participants | 152 Participants | 66 Participants |
| Region of Enrollment BRAZIL | 277 Participants | 549 Participants | 272 Participants |
| Region of Enrollment CANADA | 136 Participants | 282 Participants | 146 Participants |
| Region of Enrollment CHINA | 46 Participants | 92 Participants | 46 Participants |
| Region of Enrollment CZECH REPUBLIC | 67 Participants | 139 Participants | 72 Participants |
| Region of Enrollment FRANCE | 69 Participants | 124 Participants | 55 Participants |
| Region of Enrollment GERMANY | 46 Participants | 101 Participants | 55 Participants |
| Region of Enrollment HUNGARY | 82 Participants | 179 Participants | 97 Participants |
| Region of Enrollment ITALY | 49 Participants | 98 Participants | 49 Participants |
| Region of Enrollment MALAYSIA | 50 Participants | 92 Participants | 42 Participants |
| Region of Enrollment MEXICO | 118 Participants | 228 Participants | 110 Participants |
| Region of Enrollment NETHERLANDS | 117 Participants | 249 Participants | 132 Participants |
| Region of Enrollment NEW ZEALAND | 49 Participants | 105 Participants | 56 Participants |
| Region of Enrollment POLAND | 186 Participants | 363 Participants | 177 Participants |
| Region of Enrollment RUSSIAN FEDERATION | 213 Participants | 412 Participants | 199 Participants |
| Region of Enrollment SOUTH KOREA | 73 Participants | 167 Participants | 94 Participants |
| Region of Enrollment SPAIN | 247 Participants | 496 Participants | 249 Participants |
| Region of Enrollment SWEDEN | 118 Participants | 221 Participants | 103 Participants |
| Region of Enrollment TAIWAN | 44 Participants | 76 Participants | 32 Participants |
| Region of Enrollment UKRAINE | 213 Participants | 449 Participants | 236 Participants |
| Region of Enrollment UNITED KINGDOM | 78 Participants | 151 Participants | 73 Participants |
| Region of Enrollment UNITED STATES | 337 Participants | 673 Participants | 336 Participants |
| Sex: Female, Male Female | 1111 Participants | 2164 Participants | 1053 Participants |
| Sex: Female, Male Male | 1794 Participants | 3648 Participants | 1854 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 71 / 2,903 | 68 / 2,904 |
| other Total, other adverse events | 25 / 2,903 | 94 / 2,904 |
| serious Total, serious adverse events | 775 / 2,903 | 714 / 2,904 |
Outcome results
Primary
Progression of Albuminuria
Progression defined as the development of micro-albuminuria (Urine Albumin Creatinine Ratio \[UACR\] 30 to 300 milligram per gram \[mg/g\]) or macroalbuminuria (Albumin/creatinine ratio \[ACR\] of greater than \[\>\] 300 mg/g) in a participant with baseline normoalbuminuria (ACR less than \[\<\] 30 mg/g) or the development of macro-albuminuria in a participant with baseline microalbuminuria with an ACR increase greater than or equal to (\>=) 30 percent from baseline. Participants with macroalbuminuria at baseline (ACR\>300 mg/g) were excluded from the analysis. Event rate was estimated based on the time to the first occurrence of the event.
Time frame: Up to 3 years
Population: The intent to treat (ITT) population included all participants who were randomized. Here 'N' signifies number of participants who were evaluable for this endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Progression of Albuminuria | 153.01 Events per 1000 patient-year |
| Canagliflozin (Experimental) | Progression of Albuminuria | 99.80 Events per 1000 patient-year |
p-value: <0.000195% CI: [0.57, 0.73]Cox proportional hazard method
Secondary
Cardiovascular (CV) Death
Analyses were using adjudicated events, i.e. CV death events, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event.
Time frame: Approximately 3 years
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cardiovascular (CV) Death | 11.60 Events per 1000 patient-years |
| Canagliflozin (Experimental) | Cardiovascular (CV) Death | 10.06 Events per 1000 patient-years |
p-value: =0.406795% CI: [0.61, 1.22]Stratified Cox proportional hazard
Secondary
Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure
Analyses were using adjudicated events, that is (i.e.) CV death events or hospitalization due to heart failure, and adjudication of these outcomes by the Endpoint Adjudication Committee (EAC) were done in a blinded fashion. Event rate was estimated based on the time to the first occurrence of the event.
Time frame: Approximately 3 years
Population: ITT population included all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure | 21.91 Events per 1000 patient-years |
| Canagliflozin (Experimental) | Composite of Cardiovascular (CV) Death Events or Hospitalization for Heart Failure | 15.85 Events per 1000 patient-years |
p-value: =0.014895% CI: [0.55, 0.94]Stratified Cox proportional hazard