Diabetes Mellitus, Type 2
Conditions
Keywords
Canagliflozin, Placebo, Sitagliptin (Januvia), Metformin, Pioglitazone (Actos), Hemoglobin A1c, Type 2 diabetes mellitus
Brief summary
The purpose of this study is to evaluate the efficacy and safety of 2 different doses of canagliflozin compared with placebo in patients with type 2 diabetes mellitus who are receving treatment with metformin and pioglitazone 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), parallel-group, 3-arm (3 treatment groups) multicenter study to determine the efficacy, safety, and tolerability of canagliflozin (100 mg and 300 mg) compared to placebo (a capsule that looks like all the other treatments but has no real medicine) in patients with T2DM who are not achieving an adequate response from current antihyperglycemic therapy with metformin and pioglitazone to control their diabetes. Approximately 360 patients with T2DM who are receiving combination therapy with metformin and pioglitazone will receive the addition of once-daily treatment with canagliflozin (100 mg or 300 mg) or placebo capsules for 26 weeks followed by a 26-week extension period where patients treated with canagliflozin (100 mg or 300 mg) will continue treatment for an additional 26 weeks and patients treated with placebo will be switched to active double-blind treatment with sitagliptin 100 mg, an antihyperglycemic agent administered once-daily for 26 weeks. In addition, all patients will take protocol specified stable doses of metformin and pioglitazone along with assigned study drug for the duration of the study. Patients will participate in the study for approximately 59 to 78 weeks. During the study, if a patient's fasting blood sugar remains high despite treatment with study drug, the patient will receive treatment with glimepiride (rescue therapy) in accordance with local prescribing information. 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 (SMGB) measurements. The primary outcome measure in the study is the effect of canagliflozin relative to placebo on hemoglobin A1c (HbA1c) after 26 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 capsules for 2 weeks before randomization. After randomization, patients will take double-blind canagliflozin (100 mg or 300 mg) for 52 weeks OR placebo for 26 weeks switched to double-blind sitagliptin 100 mg for 26 weeks.
Interventions
DRUGPlacebo
One matching placebo capsule orally (by mouth) once daily for 26 weeks with stable doses of metformin and pioglitazone.
DRUGCanagliflozin
One 100 mg or 300 mg over-encapsulated tablet orally once daily for 52 weeks with stable doses of metformin and pioglitazone.
DRUGSitagliptin
One 100 mg over-encapsulated tablet orally once daily beginning at Week 26 until Week 52 with stable doses of metformin and pioglitazone.
DRUGMetformin
The patient's stable dose of metformin background therapy should be continued throughout the study.
DRUGPioglitazone
The patient's stable dose of pioglitazone background therapy should be continued throughout 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 80 Years
Healthy volunteers
No
Inclusion criteria
* All patients must have a diagnosis of T2DM and be currently treated with PPAR gamma agent ((pioglitazone or rosiglitazone) and another anti-diabetes agent (metformin) * Patients in the study must have a HbA1c between \>=7 and \<=10.5% and a fasting plasma glucose (FPG) \<270 mg/dL (15 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 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With HbA1c <7% at Week 26 | Week 26 | The table below shows the percentage of patients with HbA1c\<7% at Week 26 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage. |
| Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change. |
| Percent Change in Body Weight From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change. |
| Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | HOMA2-%B is a measure of beta cell function (the cells in the pancreas that produce and store insulin). The table below shows the least-squares (LS) mean change in HOMA2-%B from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change. |
| Percent Change in Triglycerides From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean percent change in triglycerides from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change. |
| Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean percent change in HDL-C from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change. |
| Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | Day 1 (Baseline) and Week 26 | The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change. |
Countries
Canada, Finland, France, Germany, Greece, India, Mexico, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
This study evaluated the efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus with inadequate control despite treatment with metformin and pioglitazone. The study was conducted between 13 April 2010 and 20 November 2011 and recruited patients from 74 study centers in 11 countries worldwide.
Pre-assignment details
344 patients were randomly allocated to the 3 treatment arms. 342 patients received at least 1 dose of study drug and were included in the modified intent-to-treat (mITT) analysis set (used for the Week 26 efficacy analysis) and safety analysis set (used for the Week 26 and Week 52 safety analyses).
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Sitagliptin Each patient received matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients were switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52. | 115 |
| Canagliflozin 100 mg Each patient received 100 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. | 113 |
| Canagliflozin 300 mg Each patient received 300 mg of canagliflozin once daily for 52 weeks with stable doses of metformin and pioglitazone. | 114 |
| Total | 342 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Core Period: Baseline to Week 26 | Adverse Event | 6 | 1 | 4 |
| Core Period: Baseline to Week 26 | Creatinine or eGFR withdrawal criteria | 0 | 3 | 1 |
| Core Period: Baseline to Week 26 | Lack of efficacy on rescue therapy | 1 | 0 | 0 |
| Core Period: Baseline to Week 26 | Lost to Follow-up | 1 | 1 | 2 |
| Core Period: Baseline to Week 26 | Noncompliance with study drug | 0 | 1 | 0 |
| Core Period: Baseline to Week 26 | Other | 10 | 2 | 6 |
| Core Period: Baseline to Week 26 | Protocol Violation | 1 | 0 | 0 |
| Core Period: Baseline to Week 26 | Unable to take rescue therapy | 1 | 0 | 0 |
| Core Period: Baseline to Week 26 | Withdrawal by Subject | 4 | 1 | 0 |
| Extension Period: Week 26 to Week 52 | Adverse Event | 1 | 1 | 0 |
| Extension Period: Week 26 to Week 52 | Lost to Follow-up | 1 | 0 | 0 |
| Extension Period: Week 26 to Week 52 | Noncompliance with study drug | 0 | 0 | 1 |
| Extension Period: Week 26 to Week 52 | Other | 8 | 3 | 4 |
| Extension Period: Week 26 to Week 52 | Physician Decision | 0 | 2 | 2 |
| Extension Period: Week 26 to Week 52 | Unable to take rescue therapy | 1 | 1 | 0 |
| Extension Period: Week 26 to Week 52 | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo/Sitagliptin | Canagliflozin 100 mg | Canagliflozin 300 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 32 Participants | 30 Participants | 31 Participants | 93 Participants |
| Age, Categorical Between 18 and 65 years | 83 Participants | 83 Participants | 83 Participants | 249 Participants |
| Age Continuous | 58.3 years STANDARD_DEVIATION 9.56 | 56.7 years STANDARD_DEVIATION 10.36 | 57 years STANDARD_DEVIATION 10.19 | 57.4 years STANDARD_DEVIATION 10.03 |
| Region of Enrollment CANADA | 24 participants | 22 participants | 21 participants | 67 participants |
| Region of Enrollment FINLAND | 7 participants | 3 participants | 3 participants | 13 participants |
| Region of Enrollment FRANCE | 1 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment GERMANY | 7 participants | 5 participants | 7 participants | 19 participants |
| Region of Enrollment GREECE | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment INDIA | 10 participants | 10 participants | 5 participants | 25 participants |
| Region of Enrollment MEXICO | 7 participants | 3 participants | 11 participants | 21 participants |
| Region of Enrollment SPAIN | 8 participants | 5 participants | 2 participants | 15 participants |
| Region of Enrollment THAILAND | 5 participants | 8 participants | 4 participants | 17 participants |
| Region of Enrollment UNITED KINGDOM | 3 participants | 2 participants | 3 participants | 8 participants |
| Region of Enrollment UNITED STATES | 43 participants | 55 participants | 56 participants | 154 participants |
| Sex: Female, Male Female | 39 Participants | 36 Participants | 51 Participants | 126 Participants |
| Sex: Female, Male Male | 76 Participants | 77 Participants | 63 Participants | 216 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 | 31 / 115 | 35 / 113 | 40 / 114 | 49 / 115 | 48 / 113 | 57 / 114 |
| serious Total, serious adverse events | 5 / 115 | 3 / 113 | 4 / 114 | 6 / 115 | 8 / 113 | 7 / 114 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 26
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Change in HbA1c From Baseline to Week 26 | -0.26 Percent | Standard Error 0.069 |
| Canagliflozin 100 mg | Change in HbA1c From Baseline to Week 26 | -0.89 Percent | Standard Error 0.069 |
| Canagliflozin 300 mg | Change in HbA1c From Baseline to Week 26 | -1.03 Percent | Standard Error 0.07 |
p-value: <0.00195% CI: [-0.811, -0.437]ANCOVA
p-value: <0.00195% CI: [-0.951, -0.575]ANCOVA
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26
The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | 2.54 mg/dL | Standard Error 2.785 |
| Canagliflozin 100 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | -26.8 mg/dL | Standard Error 2.796 |
| Canagliflozin 300 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 26 | -33.2 mg/dL | Standard Error 2.817 |
p-value: <0.00195% CI: [-36.96, -21.78]ANCOVA
p-value: <0.00195% CI: [-43.3, -28.11]ANCOVA
Secondary
Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26
HOMA2-%B is a measure of beta cell function (the cells in the pancreas that produce and store insulin). The table below shows the least-squares (LS) mean change in HOMA2-%B from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 | 0.91 HOMA2-%B | Standard Error 1.833 |
| Canagliflozin 100 mg | Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 | 15.19 HOMA2-%B | Standard Error 1.809 |
| Canagliflozin 300 mg | Change in Homeostasis Model Assessment (HOMA2-%B) From Baseline to Week 26 | 18.14 HOMA2-%B | Standard Error 1.79 |
p-value: <0.00195% CI: [9.315, 19.236]ANCOVA
p-value: <0.00195% CI: [12.293, 22.166]ANCOVA
Secondary
Change in Systolic Blood Pressure (SBP) From Baseline to Week 26
The table below shows the least-squares (LS) mean change in SBP from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | -1.24 mmHg | Standard Error 1.033 |
| Canagliflozin 100 mg | Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | -5.30 mmHg | Standard Error 1.036 |
| Canagliflozin 300 mg | Change in Systolic Blood Pressure (SBP) From Baseline to Week 26 | -4.70 mmHg | Standard Error 1.044 |
p-value: 0.00595% CI: [-6.879, -1.251]ANCOVA
p-value: 0.01695% CI: [-6.281, -0.643]ANCOVA
Secondary
Percentage of Patients With HbA1c <7% at Week 26
The table below shows the percentage of patients with HbA1c\<7% at Week 26 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
Time frame: Week 26
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 26 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) |
|---|---|---|
| Placebo/Sitagliptin | Percentage of Patients With HbA1c <7% at Week 26 | 32.5 Percentage of patients |
| Canagliflozin 100 mg | Percentage of Patients With HbA1c <7% at Week 26 | 46.9 Percentage of patients |
| Canagliflozin 300 mg | Percentage of Patients With HbA1c <7% at Week 26 | 64.3 Percentage of patients |
p-value: 0.00795% CI: [1.26, 4.57]Regression, Logistic
p-value: <0.00195% CI: [2.73, 10.6]Regression, Logistic
Secondary
Percent Change in Body Weight From Baseline to Week 26
The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Percent Change in Body Weight From Baseline to Week 26 | -0.1 Percent change | Standard Error 0.3 |
| Canagliflozin 100 mg | Percent Change in Body Weight From Baseline to Week 26 | -2.8 Percent change | Standard Error 0.3 |
| Canagliflozin 300 mg | Percent Change in Body Weight From Baseline to Week 26 | -3.8 Percent change | Standard Error 0.3 |
p-value: <0.00195% CI: [-3.6, -1.8]ANCOVA
p-value: <0.00195% CI: [-4.6, -2.8]ANCOVA
Secondary
Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26
The table below shows the least-squares (LS) mean percent change in HDL-C from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 2.4 Percent change | Standard Error 1.4 |
| Canagliflozin 100 mg | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 7.2 Percent change | Standard Error 1.3 |
| Canagliflozin 300 mg | Percent Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 26 | 8.9 Percent change | Standard Error 1.3 |
p-value: 0.0195% CI: [1.2, 8.5]ANCOVA
p-value: <0.00195% CI: [2.8, 10.2]ANCOVA
Secondary
Percent Change in Triglycerides From Baseline to Week 26
The table below shows the least-squares (LS) mean percent change in triglycerides from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean percent change.
Time frame: Day 1 (Baseline) and Week 26
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 26 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 |
|---|---|---|---|
| Placebo/Sitagliptin | Percent Change in Triglycerides From Baseline to Week 26 | 15.2 Percent change | Standard Error 4.1 |
| Canagliflozin 100 mg | Percent Change in Triglycerides From Baseline to Week 26 | 3.2 Percent change | Standard Error 4.1 |
| Canagliflozin 300 mg | Percent Change in Triglycerides From Baseline to Week 26 | -1.7 Percent change | Standard Error 4.1 |
p-value: 0.03495% CI: [-12.1, -0.9]ANCOVA
p-value: 0.00395% CI: [-28.1, -5.8]ANCOVA