Type 2 Diabetes
Conditions
Keywords
Dapagliflozin, efficacy, safety, sulphonylurea, Type 2 diabetes
Brief summary
This study is being carried out to see if dapagliflozin in addition to glimepiride (sulphonylurea) is effective and safe in treating patients with type 2 diabetes when compared to glimepiride alone.
Interventions
DRUGdapagliflozin
tablet oral 2.5, 5, or 10 mg total daily dose once daily 48 weeks
DRUGGlimepiride
tablet oral 2.5, 5, or 10 mg total daily dose once daily 48 weeks
DRUGmetformin hydrochloride
rescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
rescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
DRUGRosiglitazone
rescue medication oral dosing in accordance with the manufacturer's recommendations and clinical practice
Sponsors
Bristol-Myers Squibb
AstraZeneca
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 No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 Diabetes * Treatment with a stable sulphonylurea monotherapy dose that is at least half the maximal recommended dose for a minimum of 8 weeks prior to study * Inadequate glycaemic control, defined as A1C ≥ 7.0 % and ≤ 10%
Exclusion criteria
* Type 1 Diabetes * Hepatic (liver) impairment * Renal (kidney) failure or dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 24 | To assess the efficacy of dapagliflozin compared to placebo as add-on therapy to glimepiride in improving glycemic control in participants with type 2 diabetes, as determined by the change in HbA1C levels from baseline to the end of the 24-week double-blind treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in Body Weight | Baseline to Week 24 | To show that dapagliflozin plus glimepiride results in greater reduction in body weight or less weight gain after 24 weeks of treatment when compared to placebo plus glimepiride. |
| Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise | Baseline to Week 24 | To show that dapagliflozin plus glimepiride results in greater reductions in the 2-h post-challenge plasma glucose rise as a response to an oral glucose tolerance test (OGTT) from baseline to Week 24. |
| Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7% | At Week 24 | To show that dapagliflozin plus glimepiride results in a larger proportion of participants achieving a therapeutic glycemic response, defined as HbA1c \< 7% after 24 weeks of treatment, compared to placebo plus glimepiride. |
| Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2 | Baseline to Week 24 | To show that dapagliflozin plus glimepiride results in greater reductions in body weight or less weight gain in participants with baseline BMI ≥27 kg/m2 after 24 weeks of treatment when compared to placebo plus glimepiride. |
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) | Baseline to Week 24 | To show that dapagliflozin plus glimepiride leads to greater reductions in FPG after 24 weeks of treatment compared to placebo plus glimepiride. |
Countries
Czechia, Hungary, Philippines, Poland, South Korea, Thailand, Ukraine
Participant flow
Recruitment details
Enrollment: 859 (597 randomized and 592 in the Full Analysis Set) Study Start Date:April 2008 Study Completion Date:May 2010 Primary Completion Date: November 2009 (Final data collection date for primary outcome measure)
Pre-assignment details
Reasons for enrolled participants not being randomised: 229 incorrect enrollment, 4 adverse event, 23 withdrew consent, 2 lost to follow up and 4 other.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 2.5mg + Glimepiride Dapagliflozin tablet 2.5 mg once daily plus glimepiride | 154 |
| Dapagliflozin 5mg + Glimepiride Dapagliflozin tablet 5 mg once daily plus glimepiride | 142 |
| Dapagliflozin 10mg + Glimepiride Dapagliflozin tablet 10 mg once daily plus glimepiride | 151 |
| Placebo + Glimepiride Placebo comparator plus glimepiride | 145 |
| Total | 592 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 | 3 | 3 |
| Overall Study | Death | 1 | 0 | 1 | 0 |
| Overall Study | False Treatment | 0 | 1 | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 1 | 0 |
| Overall Study | Poor/Non-compliance | 0 | 3 | 0 | 0 |
| Overall Study | Subject No Longer Meets Study Criteria | 0 | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 8 | 3 | 2 | 8 |
Baseline characteristics
| Characteristic | Dapagliflozin 2.5mg + Glimepiride | Dapagliflozin 5mg + Glimepiride | Dapagliflozin 10mg + Glimepiride | Placebo + Glimepiride | Total |
|---|---|---|---|---|---|
| Age Continuous | 59.9 years STANDARD_DEVIATION 10.14 | 60.2 years STANDARD_DEVIATION 9.73 | 58.9 years STANDARD_DEVIATION 8.32 | 60.3 years STANDARD_DEVIATION 10.16 | 59.8 years STANDARD_DEVIATION 9.6 |
| BMI | 30.01 kg/m2 STANDARD_DEVIATION 5.12 | 29.84 kg/m2 STANDARD_DEVIATION 5.182 | 29.75 kg/m2 STANDARD_DEVIATION 5.641 | 29.74 kg/m2 STANDARD_DEVIATION 4.569 | 29.84 kg/m2 STANDARD_DEVIATION 5.135 |
| HbA1c | 8.11 Percent STANDARD_DEVIATION 0.749 | 8.12 Percent STANDARD_DEVIATION 0.781 | 8.07 Percent STANDARD_DEVIATION 0.79 | 8.15 Percent STANDARD_DEVIATION 0.736 | 8.11 Percent STANDARD_DEVIATION 0.763 |
| Race/Ethnicity, Customized Asian | 46 Participants | 46 Participants | 45 Participants | 44 Participants | 181 Participants |
| Race/Ethnicity, Customized White | 108 Participants | 96 Participants | 106 Participants | 101 Participants | 411 Participants |
| Sex: Female, Male Female | 77 Participants | 71 Participants | 85 Participants | 74 Participants | 307 Participants |
| Sex: Female, Male Male | 77 Participants | 71 Participants | 66 Participants | 71 Participants | 285 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 154 | 19 / 145 | 18 / 151 | 15 / 146 |
| serious Total, serious adverse events | 11 / 154 | 10 / 145 | 9 / 151 | 7 / 146 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
To assess the efficacy of dapagliflozin compared to placebo as add-on therapy to glimepiride in improving glycemic control in participants with type 2 diabetes, as determined by the change in HbA1C levels from baseline to the end of the 24-week double-blind treatment period.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Adjusted Mean Change in HbA1c Levels | -0.58 Percent |
| Dapagliflozin 5mg + Glimepiride | Adjusted Mean Change in HbA1c Levels | -0.63 Percent |
| Dapagliflozin 10mg + Glimepiride | Adjusted Mean Change in HbA1c Levels | -0.82 Percent |
| Placebo + Glimepiride | Adjusted Mean Change in HbA1c Levels | -0.13 Percent |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided)p-value: <0.000195% CI: [-0.61, -0.27]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided).p-value: <0.000195% CI: [-0.67, -0.32]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.019 applying Dunnett's adjustment, two-sided).p-value: <0.000195% CI: [-0.86, -0.51]ANCOVA
Secondary
Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise
To show that dapagliflozin plus glimepiride results in greater reductions in the 2-h post-challenge plasma glucose rise as a response to an oral glucose tolerance test (OGTT) from baseline to Week 24.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise | -37.5 mg/dL |
| Dapagliflozin 5mg + Glimepiride | Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise | -32.0 mg/dL |
| Dapagliflozin 10mg + Glimepiride | Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise | -34.9 mg/dL |
| Placebo + Glimepiride | Adjusted Mean Change in 2-h Post-challenge Plasma Glucose Rise | -6.0 mg/dL |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 095% CI: [-45, -18]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000295% CI: [-39.7, -12.3]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-42.2, -15.6]ANCOVA
Secondary
Adjusted Mean Change in Body Weight
To show that dapagliflozin plus glimepiride results in greater reduction in body weight or less weight gain after 24 weeks of treatment when compared to placebo plus glimepiride.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Adjusted Mean Change in Body Weight | -1.18 kg |
| Dapagliflozin 5mg + Glimepiride | Adjusted Mean Change in Body Weight | -1.56 kg |
| Dapagliflozin 10mg + Glimepiride | Adjusted Mean Change in Body Weight | -2.26 kg |
| Placebo + Glimepiride | Adjusted Mean Change in Body Weight | -0.72 kg |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.14195% CI: [-1.08, 0.15]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.009195% CI: [-1.47, -0.21]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-2.17, -0.92]ANCOVA
Secondary
Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2
To show that dapagliflozin plus glimepiride results in greater reductions in body weight or less weight gain in participants with baseline BMI ≥27 kg/m2 after 24 weeks of treatment when compared to placebo plus glimepiride.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with baseline BMI of 27 kg/m2 or more and Week 24 (LOCF) body weight value
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2 | -1.17 kg |
| Dapagliflozin 5mg + Glimepiride | Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2 | -1.74 kg |
| Dapagliflozin 10mg + Glimepiride | Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2 | -2.47 kg |
| Placebo + Glimepiride | Adjusted Mean Change in Body Weight for Participants With Baseline Body Mass Index (BMI)≥27 kg/m2 | -0.80 kg |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 095% CI: [-1.19, 0.45]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.026295% CI: [-1.78, -0.11]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000198% CI: [-2.5, -0.84]ANCOVA
Secondary
Adjusted Mean Change in Fasting Plasma Glucose (FPG)
To show that dapagliflozin plus glimepiride leads to greater reductions in FPG after 24 weeks of treatment compared to placebo plus glimepiride.
Time frame: Baseline to Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | -16.8 mg/dL |
| Dapagliflozin 5mg + Glimepiride | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | -21.2 mg/dL |
| Dapagliflozin 10mg + Glimepiride | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | -28.5 mg/dL |
| Placebo + Glimepiride | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | -2.0 mg/dL |
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 095% CI: [-21.8, -7.9]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-26.3, -12.2]ANCOVA
Comparison: The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-33.5, -19.5]ANCOVA
Secondary
Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7%
To show that dapagliflozin plus glimepiride results in a larger proportion of participants achieving a therapeutic glycemic response, defined as HbA1c \< 7% after 24 weeks of treatment, compared to placebo plus glimepiride.
Time frame: At Week 24
Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin 2.5mg + Glimepiride | Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7% | 26.8 Percentage of participants |
| Dapagliflozin 5mg + Glimepiride | Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7% | 30.3 Percentage of participants |
| Dapagliflozin 10mg + Glimepiride | Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7% | 31.7 Percentage of participants |
| Placebo + Glimepiride | Proportion of Participants Achieving Glycemic Response Defined as HbA1c <7% | 13.0 Percentage of participants |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 095% CI: [5.4, 22.1]Regression, Logistic
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: 0.000195% CI: [8.7, 25.9]Regression, Logistic
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: <0.000195% CI: [9.9, 27.4]Regression, Logistic