Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes, Metformin, Glimepiride, Hemoglobin A1c, Type 2 diabetes mellitus, Canagliflozin
Brief summary
The purpose of this study is to demonstrate the efficacy, safety, and tolerability of canagliflozin (JNJ-28431754) compared with glimepiride in patients with type 2 diabetes mellitus with inadequate control despite treatment with metformin.
Detailed description
Type 2 diabetes mellitus (T2DM) is well recognized as a major public health problem that presents patients with a significant risk of complications including heart disease, retinopathy, nephropathy, and neuropathy. Various classes of orally administered antihyperglycemic agents have been developed for the treatment of diabetes and although individual agents may be highly effective for some patients, it is still difficult to maintain optimal glycemic control in most patients, thereby resulting in high rates of morbidity and mortality in the diabetic population. This is a randomized, double-blind, active comparator-controlled, 3-arm, parallel-group, multicenter study to demonstrate the efficacy, safety, and tolerability of canagliflozin compared with a sulfonylurea (glimepiride) in patients with T2DM, 18 to 80 years of age, inclusive, who are not optimally controlled on metformin monotherapy. The primary study hypothesis is that the study drug will be non-inferior to glimepiride as assessed by the change in hemoglobin A1c (HbA1c) from baseline. The patients will receive capsules taken by mouth of canagliflozin (either 100 or 300 mg), or glimepiride with a starting dosage of 1 mg, which will be increased to a maximum dose of 6 or 8 mg once daily for a total duration of 104 weeks.
Interventions
DRUGGlimepiride
Glimepiride will be given orally (by mouth), as over-encapsulated tablets, starting at a dose of 1mg once daily and increasing to a maximum of 6 mg or 8 mg once daily for 104 weeks.
Canagliflozin (JNJ-28431754) will be given orally as over-encapsulated tablets, at a dose of 100 mg or 300 mg once daily for 104 weeks.
DRUGMetformin
Metformin will be given orally at the protocol-specified dose for 104 weeks.
Sponsors
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
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have a diagnosis of type 2 diabetes * Body mass index (BMI) \>=22 to \<=45 kg/m2, at screening * Patients must be taking a stable dosage of metformin as monotherapy at screening * Patients must have a HbA1c between \>=7% and \<=9.5% at Week 2 * Patients must have a fasting plasma glucose (FPG) \<=270 mg/dL (15 mmol/L) at Week -2
Exclusion criteria
* Patients having prior exposure or known contraindication or suspected hypersensitivity to JNJ-28431754, glimepiride, or metformin * History of diabetic ketoacidosis or type 1 diabetes mellitus * History of pancreas or beta-cell transplantation * History of active proliferative diabetic retinopathy * History of hereditary glucose-galactose malabsorption or primary renal glucosuria * Renal disease requiring treatment with immunosuppressive therapy within the past 12 months before screening or a history of dialysis or renal transplant * Taken thiazolidinedione therapy in the past 16 weeks before screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the percentage of patients who experienced at least 1 documented hypoglycemic event from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in percentages. |
| Percent Change in Body Weight From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean percent change. |
| Change in HbA1c From Baseline to Week 104 | Baseline, Week 104 | The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 104 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean change. |
Countries
Argentina, Bulgaria, Canada, Costa Rica, Denmark, Finland, Germany, India, Israel, Mexico, Norway, Philippines, Poland, Puerto Rico, Romania, Russia, Slovakia, South Korea, Ukraine, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of canagliflozin (JNJ-28431754) compared with glimepiride in participants with type 2 diabetes mellitus with inadequate glycemic control despite metformin treatment. The study was conducted between 28 August 2009 and 25 January 2013 and included 157 study centers in 19 countries worldwide.
Pre-assignment details
1,452 participants were randomly allocated to the 3 treatment arms. 1450 participants received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set and safety analysis set. Participant flow is presented for Baseline to Week 104.
Participants by arm
| Arm | Count |
|---|---|
| Canagliflozin 100 mg Each patient received 100 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. | 483 |
| Canagliflozin 300 mg Each patient received 300 mg of canagliflozin (JNJ-28431754) once daily with protocol-specified doses of metformin for 104 weeks. | 485 |
| Glimepiride Each patient received glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks. | 482 |
| Total | 1,450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 30 | 46 | 33 |
| Overall Study | Creatinine or eGFR withdrawal criteria | 9 | 13 | 7 |
| Overall Study | Death | 2 | 2 | 1 |
| Overall Study | Lack of Efficacy | 9 | 7 | 16 |
| Overall Study | Lost to Follow-up | 17 | 12 | 11 |
| Overall Study | Noncompliance with study drug | 4 | 1 | 6 |
| Overall Study | Other | 25 | 37 | 40 |
| Overall Study | Physician Decision | 8 | 5 | 9 |
| Overall Study | Protocol Violation | 7 | 4 | 3 |
| Overall Study | Unable to take rescue therapy | 12 | 12 | 17 |
| Overall Study | Withdrawal by Subject | 17 | 23 | 25 |
Baseline characteristics
| Characteristic | Canagliflozin 300 mg | Glimepiride | Canagliflozin 100 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 74 Participants | 83 Participants | 86 Participants | 243 Participants |
| Age, Categorical Between 18 and 65 years | 411 Participants | 399 Participants | 397 Participants | 1207 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 9.17 | 56.3 years STANDARD_DEVIATION 9.01 | 56.4 years STANDARD_DEVIATION 9.49 | 56.2 years STANDARD_DEVIATION 9.22 |
| Gender Female | 244 Participants | 219 Participants | 231 Participants | 694 Participants |
| Gender Male | 241 Participants | 263 Participants | 252 Participants | 756 Participants |
| Region Enroll ARGENTINA | 18 participants | 18 participants | 18 participants | 54 participants |
| Region Enroll BULGARIA | 7 participants | 7 participants | 7 participants | 21 participants |
| Region Enroll CANADA | 20 participants | 19 participants | 19 participants | 58 participants |
| Region Enroll COSTA RICA | 9 participants | 9 participants | 10 participants | 28 participants |
| Region Enroll DENMARK | 25 participants | 25 participants | 24 participants | 74 participants |
| Region Enroll FINLAND | 17 participants | 19 participants | 18 participants | 54 participants |
| Region Enroll GERMANY | 7 participants | 6 participants | 6 participants | 19 participants |
| Region Enroll INDIA | 55 participants | 56 participants | 55 participants | 166 participants |
| Region Enroll ISRAEL | 15 participants | 14 participants | 14 participants | 43 participants |
| Region Enroll MEXICO | 25 participants | 24 participants | 24 participants | 73 participants |
| Region Enroll NORWAY | 9 participants | 9 participants | 9 participants | 27 participants |
| Region Enroll PHILIPPINES | 13 participants | 13 participants | 14 participants | 40 participants |
| Region Enroll POLAND | 15 participants | 15 participants | 14 participants | 44 participants |
| Region Enroll ROMANIA | 43 participants | 44 participants | 43 participants | 130 participants |
| Region Enroll RUSSIAN FEDERATION | 22 participants | 22 participants | 23 participants | 67 participants |
| Region Enroll SLOVAKIA | 14 participants | 13 participants | 15 participants | 42 participants |
| Region Enroll SOUTH KOREA | 32 participants | 31 participants | 31 participants | 94 participants |
| Region Enroll UKRAINE | 22 participants | 22 participants | 22 participants | 66 participants |
| Region Enroll UNITED STATES | 117 participants | 116 participants | 117 participants | 350 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 138 / 483 | 150 / 485 | 175 / 482 | 198 / 483 | 204 / 485 | 242 / 482 |
| serious Total, serious adverse events | 24 / 483 | 26 / 485 | 39 / 482 | 47 / 483 | 47 / 485 | 69 / 482 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 52
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 52 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 100 mg | Change in HbA1c From Baseline to Week 52 | -0.82 Percent | Standard Error 0.039 |
| Canagliflozin 300 mg | Change in HbA1c From Baseline to Week 52 | -0.93 Percent | Standard Error 0.039 |
| Glimepiride | Change in HbA1c From Baseline to Week 52 | -0.81 Percent | Standard Error 0.039 |
Comparison: If the hypothesis of non-inferiority of canagliflozin to glimepiride at Week 52 was demonstrated (ie, upper bound of the 95% Confidence Interval of the treatment difference \[canagliflozin minus glimepiride\] was less than 0.3) and the upper bound was less than 0.0, the superiority of the canagliflozin dose relative to glimepiride would be concluded.95% CI: [-0.109, 0.085]ANCOVA
Comparison: If the hypothesis of non-inferiority of canagliflozin to glimepiride at Week 52 was demonstrated (ie, upper bound of the 95% Confidence Interval of the treatment difference \[canagliflozin minus glimepiride\] was less than 0.3) and the upper bound was less than 0.0, the superiority of the canagliflozin dose relative to glimepiride would be concluded.95% CI: [-0.217, -0.023]ANCOVA
Secondary
Change in HbA1c From Baseline to Week 104
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 104 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean change.
Time frame: Baseline, Week 104
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 100 mg | Change in HbA1c From Baseline to Week 104 | -0.65 Percent | Standard Error 0.042 |
| Canagliflozin 300 mg | Change in HbA1c From Baseline to Week 104 | -0.74 Percent | Standard Error 0.042 |
| Glimepiride | Change in HbA1c From Baseline to Week 104 | -0.55 Percent | Standard Error 0.043 |
95% CI: [-0.2, 0.01]ANCOVA
95% CI: [-0.289, -0.078]ANCOVA
Secondary
Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52
The table below shows the percentage of patients who experienced at least 1 documented hypoglycemic event from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in percentages.
Time frame: Day 1 (Baseline) and Week 52
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 52 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canagliflozin 100 mg | Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52 | 5.6 Percentage of patients |
| Canagliflozin 300 mg | Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52 | 4.9 Percentage of patients |
| Glimepiride | Percentage of Patients Experiencing at Least 1 Hypoglycemic Event From Baseline to Week 52 | 34.2 Percentage of patients |
p-value: <0.00195% CI: [0.06, 0.16]Regression, Logistic
p-value: <0.00195% CI: [0.05, 0.14]Regression, Logistic
Secondary
Percent Change in Body Weight From Baseline to Week 52
The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 52 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus glimepiride) in the LS mean percent change.
Time frame: Day 1 (Baseline) and Week 52
Population: Analysis used mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 52 values. Measurements taken pre-rescue used as last observation in patients receiving glycemic rescue therapy. Table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 100 mg | Percent Change in Body Weight From Baseline to Week 52 | -4.2 Percent change | Standard Error 0.2 |
| Canagliflozin 300 mg | Percent Change in Body Weight From Baseline to Week 52 | -4.7 Percent change | Standard Error 0.2 |
| Glimepiride | Percent Change in Body Weight From Baseline to Week 52 | 1.0 Percent change | Standard Error 0.2 |
p-value: <0.00195% CI: [-5.7, -4.7]ANCOVA
p-value: <0.00195% CI: [-6.2, -5.1]ANCOVA