Cardiovascular Disease, Inadequate Glycaemic Control, Type 2 Diabetes Mellitus
Conditions
Keywords
dapagliflozin, diabetes, cardiovascular disease
Brief summary
This study is carried out to assess whether dapagliflozin improves glycemic control, decreases fasting plasma glucose levels, body weight and blood pressure when added to patient's existing medications and how it compares with their usual treatment without added dapagliflozin. Safety data will be collected and analysed to confirm that treatment with dapagliflozin is safe and well tolerated in patients who have diabetes and cardiovascular disease
Interventions
DRUGDapagliflozin
10 mg tablet, oral, once daily, 24- week treatment and 80-week extension period
DRUGPlacebo
matching placebo tablet, oral, once daily, 24- week treatment and 80-week extension period
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
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus. * Cardiovascular disease * Uninterrupted anti-diabetic treatment for at least 8 weeks before enrolment
Exclusion criteria
* Patients with type 1 diabetes or diabetes insipidus * Patients with 3 or more oral anti-hyperglycaemic drugs with or without insulin and/or poorly controlled diabetes * Any clinically significant illness, which would compromise the patient's safety and their participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 24 | To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, measured as the mean change in HbA1c from baseline to week 24. |
| Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit | Baseline to Week 24 | To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF) | Baseline to Week 8 | To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo. |
| Adjusted Mean Percent Change in Body Weight | Baseline to Week 24 | To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo. |
| Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg | Baseline to Week 8 | To compare the mean change in seated systolic blood pressure (SBP) in participants with baseline seated SBP ≥130 mmHg achieved with dapagliflozin versus placebo from baseline to week 8. |
| Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF) | Baseline to Week 24 | To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo. |
| Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m² | Baseline to Week 24 | To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum. |
Countries
Argentina, Australia, Austria, Bulgaria, Canada, Chile, Germany, Hungary, Poland, United States
Participant flow
Recruitment details
First participant enrolled 15 Mar 2010, last part. last visit for 24-week period: 30 May 2011. 1489 part. enrolled, 964 randomized in USA, Canada, Australia, Chile, Argentina and 5 European countries (value presented in 'Enrolment' field). One add. part. treated but not randomized. Part. with T2DM and CVD who showed inadequate glycemic control.
Pre-assignment details
During a placebo lead-in period, participants were counselled on dietary and life-style modifications. Anti-diabetic therapy should be kept constant 4 weeks prior to enrolment. Participants eligible for the study were stratified according to age (\<65 years or ≥65 years), insulin use and time from most recent qualifying CV event (\>1 or ≤1 year).
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin Dapagliflozin 10 mg plus usual care | 480 |
| Placebo Placebo plus usual care | 482 |
| Total | 962 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reason by sponsor | 0 | 1 |
| Overall Study | Adverse Event | 4 | 12 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Incorrect enrollment | 6 | 4 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Poor/non-compliance | 3 | 4 |
| Overall Study | Safety | 0 | 2 |
| Overall Study | Subject no longer meets study criteria | 15 | 13 |
| Overall Study | Various | 3 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 16 |
Baseline characteristics
| Characteristic | Placebo | Total | Dapagliflozin |
|---|---|---|---|
| Age, Continuous | 63.6 Years STANDARD_DEVIATION 7.02 | 63.8 Years STANDARD_DEVIATION 7.31 | 63.9 Years STANDARD_DEVIATION 7.6 |
| Body weight | 93.23 kg STANDARD_DEVIATION 16.842 | 93.88 kg STANDARD_DEVIATION 17.332 | 94.53 kg STANDARD_DEVIATION 17.804 |
| HbA1c | 8.08 Percent STANDARD_DEVIATION 0.795 | 8.06 Percent STANDARD_DEVIATION 0.777 | 8.04 Percent STANDARD_DEVIATION 0.759 |
| Number of participants with BMI >= 27 kg/m2 at baseline < 25 kg/m² | 31 Participants | 46 Participants | 15 Participants |
| Number of participants with BMI >= 27 kg/m2 at baseline >= 25 kg/m² | 451 Participants | 916 Participants | 465 Participants |
| Number of participants with BMI >= 27 kg/m2 at baseline >= 27 kg/m² | 416 Participants | 844 Participants | 428 Participants |
| Number of participants with BMI >= 27 kg/m2 at baseline >= 30 kg/m² | 325 Participants | 664 Participants | 339 Participants |
| Race/Ethnicity, Customized Asian | 7 Participants | 13 Participants | 6 Participants |
| Race/Ethnicity, Customized Black/African American | 10 Participants | 19 Participants | 9 Participants |
| Race/Ethnicity, Customized Other | 16 Participants | 27 Participants | 11 Participants |
| Race/Ethnicity, Customized White | 449 Participants | 903 Participants | 454 Participants |
| Sex: Female, Male Female | 159 Participants | 318 Participants | 159 Participants |
| Sex: Female, Male Male | 323 Participants | 644 Participants | 321 Participants |
| Systolic Blood Pressure | 134.6 mmHg STANDARD_DEVIATION 13.96 | 134.7 mmHg STANDARD_DEVIATION 14.24 | 134.9 mmHg STANDARD_DEVIATION 14.53 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 147 / 482 | 134 / 483 |
| serious Total, serious adverse events | 41 / 482 | 46 / 483 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, measured as the mean change in HbA1c 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) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Adjusted Mean Change in HbA1c Levels | -0.33 Percent | 95% Confidence Interval 0.0434 |
| Placebo | Adjusted Mean Change in HbA1c Levels | 0.07 Percent | — |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-0.5, -0.3]ANCOVA
Primary
Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit
To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.
Time frame: Baseline to Week 24
Population: Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit | 10.0 Percentage of participants | 95% Confidence Interval 0.7 |
| Placebo | Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit | 1.9 Percentage of participants | 95% Confidence Interval 7.3 |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: <0.000195% CI: [4.3, 9.8]Cochran-Mantel-Haenszel
Secondary
Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF)
To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time frame: Baseline to Week 24
Population: Full Analysis set, subjects with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF) | -2.70 mmHg | 95% Confidence Interval 0.7109 |
| Placebo | Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF) | 0.32 mmHg | 95% Confidence Interval 0.714 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000295% CI: [-4.59, -1.46]ANCOVA
Secondary
Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg
To compare the mean change in seated systolic blood pressure (SBP) in participants with baseline seated SBP ≥130 mmHg achieved with dapagliflozin versus placebo from baseline to week 8.
Time frame: Baseline to Week 8
Population: Full Analysis set, participants with baseline seated SBP ≥130 mmHg and Week 8 (LOCF) value
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg | -5.33 mmHg | 95% Confidence Interval 0.8612 |
| Placebo | Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg | -1.89 mmHg | 95% Confidence Interval 0.8612 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000495% CI: [-5.35, -1.53]ANCOVA
Secondary
Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF)
To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.
Time frame: Baseline to Week 8
Population: Full Analysis Set, subjects with non-missing baseline and Week 8 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF) | -1.85 mmHg | 95% Confidence Interval 0.7105 |
| Placebo | Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF) | 0.86 mmHg | 95% Confidence Interval 0.7135 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: 0.000795% CI: [-4.28, -1.15]ANCOVA
Secondary
Adjusted Mean Percent Change in Body Weight
To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time frame: Baseline to Week 24
Population: Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Adjusted Mean Percent Change in Body Weight | -2.53 Percentage of Body Weight | 95% Confidence Interval 0.177 |
| Placebo | Adjusted Mean Percent Change in Body Weight | -0.61 Percentage of Body Weight | 95% Confidence Interval 0.1736 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0p-value: <0.000195% CI: [-2.31, -1.54]ANCOVA
Secondary
Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m²
To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.
Time frame: Baseline to Week 24
Population: Full Analysis Set, subjects with baseline BMI ≥27 kg/m2 and Week 24 (LOCF) values
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m² | 18.4 Percentage of participants | 95% Confidence Interval 1.051 |
| Placebo | Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m² | 4.8 Percentage of participants | 95% Confidence Interval 1.876 |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0p-value: <0.000195% CI: [9.4, 17.8]Regression, Logistic