Diabetes Mellitus, Type 2
Conditions
Keywords
Canagliflozin, Placebo, Type 2 diabetes mellitus
Brief summary
The purpose of this study is to assess the safety, tolerability, and efficacy of the addition of canagliflozin relative to the addition of placebo in patients with inadequate glycemic control on metformin alone or in combination with a sulphonylurea.
Detailed description
This is a double-blind (neither study staff or the patient will know the identity of the treatment assigned) study of canagliflozin where Chinese and other Asian adult patients with Type 2 Diabetes Mellitus (T2DM) who have inadequate glycemic control on metformin alone or in combination with a sulphonylurea (SU) will be randomized (assigned to 1 of 3 treatments by chance) to receive the addition of treatment with canagliflozin 100 mg once daily, canagliflozin 300 mg once daily, or matching placebo capsules (placebo is a treatment identical in appearance to canagliflozin but does not contain active drug). All patients will take orally (by mouth) 1 single-blind placebo capsule once daily before the first meal of the day for up to 2 weeks (last dose of single-blind placebo to be taken the day before the baseline (Day 1) visit. On Day 1, patients will take orally, once daily 1 capsule of canagliflozin 100 mg, canagliflozin 300 mg, or placebo before the first meal of the day for up to 18 weeks.
Interventions
DRUGPlacebo
Form=capsule, route=oral administration. One capsule once daily for up to 18 weeks after completing a single-blind placebo run-in period (1 placebo capsule once daily for up to 2 weeks).
Type=1, unit=mg, number=100, form=capsule, route=oral use. One capsule once daily for up to 18 weeks after completing a single-blind placebo run-in period (1 placebo capsule once daily for up to 2 weeks).
Type=1, unit=mg, number=300, form=capsule, route=oral use. One capsule once daily for up to 18 weeks after completing a single-blind placebo run-in period (1 placebo capsule once daily for up to 2 weeks).
DRUGMetformin
The participant's stable dose of background therapy of metformin should be continued throughout the study.
DRUGSulphonylurea
The participant's stable dose of background therapy of metformin plus sulphonylurea should be continued throughout the study.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients with T2DM with inadequate glycemic control on metformin monotherapy or on metformin in combination with an SU at protocol-specified doses and having HbA1c \>=7.0% and \<=10.5% at Week -2 are eligible for enrollment in the study.
Exclusion criteria
* History of diabetic ketoacidosis, type 1 diabetes mellitus (T1DM), pancreas or beta cell transplantation, or diabetes secondary to pancreatitis or pancreatectomy * Has repeated (ie, 2 or more over a 1-week period) fasting plasma glucose (FPG) and/or fasting self-monitored blood glucose (SMBG) measurements \>=270 mg/dL (15 mmol/L) during the pre-treatment phase, despite reinforcement of diet and exercise counseling * History of a severe hypoglycemic episode within 6 months before screening * History of or current illness considered to be clinically significant by the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 18 | Day 1 (Baseline) and Week 18 | The table below shows the least-squares (LS) mean change in HbA1c from baseline to Week 18 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 |
|---|---|---|
| Percent Change in Body Weight From Baseline to Week 18 | Day 1 (Baseline) and Week 18 | The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 18 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 Fasting Plasma Glucose (FPG) From Baseline to Week 18 | Day 1 (Baseline) and Week 18 | The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 18 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change. |
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <7% at Week 18 | Day 1 (Baseline) and Week 18 | The table below shows the percentage of patients with HbA1c \<7% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage. |
| Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <6.5% at Week 18 | Day 1 (Baseline) and Week 18 | The table below shows the percentage of patients with HbA1c \<6.5% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage. |
Countries
China, Malaysia, Vietnam
Participant flow
Recruitment details
This study evaluated the efficacy and safety of canagliflozin in Asian participants with type 2 diabetes mellitus who had inadequate glycemic control on a maximally effective or tolerated dose of metformin alone or metformin plus sulphonylurea (SU). It was conducted between 30 June 2011 and 21 December 2012 and recruited patients from 36 sites.
Pre-assignment details
The study had two background treatment strata: 331 participants in the metformin alone stratum and 347 in the metformin plus SU. In total, 678 participants were randomly allocated to the 3 treatment arms, 676 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 |
|---|---|
| Placebo Each participant received matching placebo once daily for 18 weeks with protocol-specified doses of metformin alone or metformin plus sulphonylurea. | 226 |
| Canagliflozin 100 mg Each participant received 100 mg of canagliflozin once daily for 18 weeks with protocol-specified doses of metformin alone or metformin plus sulphonylurea. | 223 |
| Canagliflozin 300 mg Each participant received 300 mg of canagliflozin once daily for 18 weeks with protocol-specified doses of metformin alone or metformin plus sulphonylurea. | 227 |
| Total | 676 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 7 |
| Overall Study | Early withdraw | 3 | 1 | 1 |
| Overall Study | Noncompliance with study drug | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Subject meets glycemic withdrawal crit. | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Canagliflozin 100 mg | Canagliflozin 300 mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 42 Participants | 36 Participants | 41 Participants | 119 Participants |
| Age, Categorical Between 18 and 65 years | 184 Participants | 187 Participants | 186 Participants | 557 Participants |
| Age, Continuous | 55.8 years STANDARD_DEVIATION 9.35 | 56.5 years STANDARD_DEVIATION 8.25 | 56.4 years STANDARD_DEVIATION 9.21 | 56.3 years STANDARD_DEVIATION 8.94 |
| Region Enroll China | 213 participants | 210 participants | 213 participants | 636 participants |
| Region Enroll Malaysia | 3 participants | 5 participants | 4 participants | 12 participants |
| Region Enroll Vietnam | 10 participants | 8 participants | 10 participants | 28 participants |
| Sex: Female, Male Female | 101 Participants | 99 Participants | 114 Participants | 314 Participants |
| Sex: Female, Male Male | 125 Participants | 124 Participants | 113 Participants | 362 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 226 | 27 / 223 | 27 / 227 |
| serious Total, serious adverse events | 4 / 226 | 5 / 223 | 4 / 227 |
Outcome results
Primary
Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 18
The table below shows the least-squares (LS) mean change in HbA1c from baseline to Week 18 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 18
Population: Analysis used overall mITT analysis set (all randomized patients who received at least 1 dose of double-blind study drug). Last-observation-carried-forward method used for missing Week 18 values. Table includes only participants with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 18 | -0.47 Percent | Standard Error 0.096 |
| Canagliflozin 100 mg | Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 18 | -0.97 Percent | Standard Error 0.095 |
| Canagliflozin 300 mg | Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 18 | -1.06 Percent | Standard Error 0.095 |
p-value: <0.00195% CI: [-0.644, -0.367]ANCOVA
p-value: <0.00195% CI: [-0.731, -0.453]ANCOVA
Secondary
Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18
The table below shows the least-squares (LS) mean change in FPG from Baseline to Week 18 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 18
Population: Analysis used overall mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 18 values. Table includes only participants with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18 | -0.40 mg/dL | Standard Error 0.237 |
| Canagliflozin 100 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18 | -1.44 mg/dL | Standard Error 0.236 |
| Canagliflozin 300 mg | Change in Fasting Plasma Glucose (FPG) From Baseline to Week 18 | -1.83 mg/dL | Standard Error 0.235 |
p-value: <0.00195% CI: [-1.375, -0.694]ANCOVA
p-value: <0.00195% CI: [-1.769, -1.089]ANCOVA
Secondary
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <6.5% at Week 18
The table below shows the percentage of patients with HbA1c \<6.5% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
Time frame: Day 1 (Baseline) and Week 18
Population: Analysis used overall mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 18 values. Table includes only participants with both baseline and post baseline values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <6.5% at Week 18 | 11.7 Percentage of patients |
| Canagliflozin 100 mg | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <6.5% at Week 18 | 21.6 Percentage of patients |
| Canagliflozin 300 mg | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <6.5% at Week 18 | 25.3 Percentage of patients |
95% CI: [1.45, 4.48]Regression, Logistic
95% CI: [1.88, 5.75]Regression, Logistic
Secondary
Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <7% at Week 18
The table below shows the percentage of patients with HbA1c \<7% at Week 18 in each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the percentage.
Time frame: Day 1 (Baseline) and Week 18
Population: Analysis used overall mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 18 values. Table includes only participants with both baseline and post baseline values.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <7% at Week 18 | 27.8 Percentage of patients |
| Canagliflozin 100 mg | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <7% at Week 18 | 49.1 Percentage of patients |
| Canagliflozin 300 mg | Percentage of Patients With Glycosylated Hemoglobin (HbA1c) <7% at Week 18 | 52.9 Percentage of patients |
95% CI: [2.09, 5.09]Regression, Logistic
95% CI: [2.55, 6.27]Regression, Logistic
Secondary
Percent Change in Body Weight From Baseline to Week 18
The table below shows the least-squares (LS) mean percent change in body weight from Baseline to Week 18 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 18
Population: Analysis used overall mITT analysis set (all randomized patients who received at least 1 dose of study drug). Last-observation-carried-forward method used for missing Week 18 values. Table includes only participants with both baseline and post baseline values.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change in Body Weight From Baseline to Week 18 | -0.8 Pecent change | Standard Error 0.4 |
| Canagliflozin 100 mg | Percent Change in Body Weight From Baseline to Week 18 | -2.9 Pecent change | Standard Error 0.4 |
| Canagliflozin 300 mg | Percent Change in Body Weight From Baseline to Week 18 | -3.1 Pecent change | Standard Error 0.4 |
p-value: <0.00195% CI: [-2.7, -1.6]ANCOVA
p-value: <0.00195% CI: [-2.9, -1.8]ANCOVA