Diabetes Mellitus, Type 2
Conditions
Keywords
Canagliflozin, Sitagliptin (Januvia), Metformin, Sulphonylurea, Hemoglobin A1c, Type 2 diabetes mellitus
Brief summary
The purpose of this study is to evaluate the efficacy and safety of canagliflozin compared with sitagliptin in patients with type 2 diabetes mellitus who are receiving treatment with metformin and sulphonylurea and have inadequate glycemic (blood sugar) control.
Detailed description
Canagliflozin is a drug that is being tested to see if it may be useful in treating patients diagnosed with type 2 diabetes mellitus (T2DM). This is a randomized (study drug assigned by chance), double-blind (neither the patient or the study doctor will know the name of the assigned treatment), multicenter study to determine the efficacy, safety, and tolerability of canagliflozin 300 mg compared to sitagliptin 100 mg (an antihyperglycemic drug) in patients with T2DM who are not achieving an adequate response from current antihyperglycemic therapy with metformin and sulphonylurea to control their diabetes. Approximately 720 patients with T2DM who are receiving combination therapy with metformin and sulphonylurea will receive the addition of once-daily treatment with canagliflozin 300 mg or sitagliptin 100 mg capsules for 52 weeks. Patients will participate in the study for approximately 59 to 72 weeks. During treatment, patients will be monitored for safety by review of adverse events, results from laboratory tests, 12-lead electrocardiograms (ECGs), vital signs measurements, body weight, physical examinations, and self monitored blood glucose (SMBG) measurements. The primary outcome measure in the study is the effect of canagliflozin compared to sitagliptin on hemoglobin A1c (HbA1c) after 52 weeks of treatment. Study drug will be taken orally (by mouth) once daily before the first meal each day unless otherwise specified. Patients will take single-blind placebo for 2 weeks before randomization. After randomization, patients in the study will take double-blind canagliflozin 300 mg or matching sitagliptin 100 mg for 52 weeks.
Interventions
One 100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea
One 300 mg capsule once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea
DRUGMetformin
Patients will continue to take background therapy with Metformin for T2DM at maximally or near-maximally effective protocol-specified doses for the duration of the study.
DRUGSulphonylurea
Patients will continue to take background therapy with Sulphonylurea for T2DM at maximally or near-maximally effective protocol-specified doses for the duration of the study.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All patients must have a diagnosis of T2DM and be currently treated with metformin and sulphonylurea * Patients in the study must have a HbA1c between \>=7 and \<=10.5% and a fasting plasma glucose (FPG) \<300 mg/dL (16.7 mmol/L)
Exclusion criteria
* History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy * or a severe hypoglycemic episode within 6 months 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 analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change. |
| 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 analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean percent change. |
| Percentage of Patients With HbA1c <7% at Week 52 | Week 52 | The table below shows the percentage of patients with HbA1c \<7% at Week 52 in each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the percentage. |
| Percent Change in Triglycerides From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the mean percent change in triglycerides from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change. |
| Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the mean percent change in HDL-C from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change. |
| Change in Systolic Blood Pressure (SBP) From Baseline to Week 52 | Day 1 (Baseline) and Week 52 | The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change. |
Countries
Austria, Belgium, Brazil, Canada, Denmark, France, Germany, India, Israel, Malaysia, Netherlands, New Zealand, Poland, Singapore, South Korea, Ukraine, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of canagliflozin compared with sitaglitin in patients with type 2 diabetes mellitus with inadequate control, despite treatment with metformin and sulphonylureas. The study was conducted between 30 June 2010 and 09 March 2012 and recruited patients from 140 study centers located in 17 countries worldwide.
Pre-assignment details
A total of 756 patients were randomly allocated to the 2 treatment arms in the study. 755 patients received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set and the safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| Canagliflozin 300 mg Each patient received 300 mg of canagliflozin once a day for 52 weeks with protocol-specified doses of metformin and sulphonylurea. | 377 |
| Sitagliptin 100 mg Each patient received 100 mg of sitagliptin once a day for 52 weeks with protocol-specified doses of metformin and sulphonylurea. | 378 |
| Total | 755 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 21 | 14 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 6 | 8 |
| Overall Study | Other | 19 | 27 |
| Overall Study | Patient met glycemic withdrawal criteria | 40 | 85 |
| Overall Study | Physician Decision | 25 | 17 |
| Overall Study | Protocol Violation | 5 | 4 |
| Overall Study | Withdrawal by Subject | 5 | 13 |
Baseline characteristics
| Characteristic | Canagliflozin 300 mg | Total | Sitagliptin 100 mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 73 Participants | 144 Participants | 71 Participants |
| Age, Categorical Between 18 and 65 years | 304 Participants | 611 Participants | 307 Participants |
| Age, Continuous | 56.5 years STANDARD_DEVIATION 9.62 | 56.5 years STANDARD_DEVIATION 9.47 | 56.6 years STANDARD_DEVIATION 9.33 |
| Region Treated AUSTRIA | 4 participants | 6 participants | 2 participants |
| Region Treated BELGIUM | 3 participants | 5 participants | 2 participants |
| Region Treated BRAZIL | 76 participants | 156 participants | 80 participants |
| Region Treated CANADA | 41 participants | 86 participants | 45 participants |
| Region Treated DENMARK | 2 participants | 7 participants | 5 participants |
| Region Treated FRANCE | 5 participants | 11 participants | 6 participants |
| Region Treated GERMANY | 5 participants | 10 participants | 5 participants |
| Region Treated INDIA | 33 participants | 56 participants | 23 participants |
| Region Treated ISRAEL | 7 participants | 10 participants | 3 participants |
| Region Treated MALAYSIA | 10 participants | 24 participants | 14 participants |
| Region Treated NETHERLANDS | 2 participants | 3 participants | 1 participants |
| Region Treated NEW ZEALAND | 11 participants | 24 participants | 13 participants |
| Region Treated POLAND | 20 participants | 45 participants | 25 participants |
| Region Treated SINGAPORE | 2 participants | 4 participants | 2 participants |
| Region Treated SOUTH KOREA | 7 participants | 19 participants | 12 participants |
| Region Treated UKRAINE | 27 participants | 46 participants | 19 participants |
| Region Treated UNITED STATES | 122 participants | 243 participants | 121 participants |
| Sex: Female, Male Female | 170 Participants | 333 Participants | 163 Participants |
| Sex: Female, Male Male | 207 Participants | 422 Participants | 215 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 377 | 159 / 378 |
| serious Total, serious adverse events | 24 / 377 | 21 / 378 |
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 analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Change in HbA1c From Baseline to Week 52 | -1.03 Percent | Standard Error 0.048 |
| Sitagliptin 100 mg | Change in HbA1c From Baseline to Week 52 | -0.66 Percent | Standard Error 0.049 |
Comparison: If the hypothesis of non-inferiority of canagliflozin to sitagliptin at Week 52 was demonstrated (ie, upper bound of the 95% Confidence Interval of the treatment difference \[canagliflozin minus sitagliptin\] was less than 0.3) and the upper bound was less than 0.0, the superiority of the canagliflozin dose relative to sitagliptin would be concluded.p-value: <0.0595% CI: [-0.5, -0.25]ANCOVA
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52
The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | -29.9 mg/dL | Standard Error 2.201 |
| Sitagliptin 100 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 52 | -5.85 mg/dL | Standard Error 2.232 |
p-value: <0.00195% CI: [-29.89, -18.24]ANCOVA
Secondary
Change in Systolic Blood Pressure (SBP) From Baseline to Week 52
The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Change in Systolic Blood Pressure (SBP) From Baseline to Week 52 | -5.06 mmHg | Standard Error 0.656 |
| Sitagliptin 100 mg | Change in Systolic Blood Pressure (SBP) From Baseline to Week 52 | 0.85 mmHg | Standard Error 0.666 |
p-value: <0.00195% CI: [-7.642, -4.175]ANCOVA
Secondary
Percentage of Patients With HbA1c <7% at Week 52
The table below shows the percentage of patients with HbA1c \<7% at Week 52 in each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the percentage.
Time frame: Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Canagliflozin 300 mg | Percentage of Patients With HbA1c <7% at Week 52 | 47.6 Percentage of patients |
| Sitagliptin 100 mg | Percentage of Patients With HbA1c <7% at Week 52 | 35.3 Percentage of patients |
95% CI: [1.3, 2.48]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 analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean percent change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Percent Change in Body Weight From Baseline to Week 52 | -2.5 Percent change | Standard Error 0.2 |
| Sitagliptin 100 mg | Percent Change in Body Weight From Baseline to Week 52 | 0.3 Percent change | Standard Error 0.2 |
p-value: <0.00195% CI: [-3.3, -2.2]ANCOVA
Secondary
Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 52
The table below shows the mean percent change in HDL-C from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 52 | 7.6 Percent change | Standard Error 0.9 |
| Sitagliptin 100 mg | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 52 | 0.6 Percent change | Standard Error 0.9 |
p-value: <0.00195% CI: [4.6, 9.3]ANCOVA
Secondary
Percent Change in Triglycerides From Baseline to Week 52
The table below shows the mean percent change in triglycerides from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 52
Population: This analysis used the modified intent-to-treat analysis set (all patients who were randomly assigned to a treatment group and received at least 1 dose of study drug). The last-observation-carried-forward method was applied when the Week 52 values were missing. The table includes only patients with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Canagliflozin 300 mg | Percent Change in Triglycerides From Baseline to Week 52 | 9.6 Percent change | Standard Error 2.8 |
| Sitagliptin 100 mg | Percent Change in Triglycerides From Baseline to Week 52 | 11.9 Percent change | Standard Error 2.9 |
p-value: 0.55495% CI: [-9.8, 5.3]ANCOVA