Type 2 Diabetes
Conditions
Keywords
Dapagliflozin DPP IV inhibitor add on study, Inadequate control
Brief summary
This study aims to investigate how dapagliflozin can control blood sugar in patients with type 2 diabetes when added to existing treatments (sitagliptin alone or in combination with metformin). The effect of dapagliflozin on weight and blood pressure will also be studied.
Interventions
DRUGDapagliflozin
10 mg tablet, oral, once daily, 48 weeks
DRUGPlacebo
Matching placebo tablet
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
* Patients with type 2 diabetes * Patients who are not receiving treatment , or those who currently receive metformin, sitagliptin or vildagliptin or the combination of these * Patients will be screened by a blood test and only those who need additional therapy can be enrolled
Exclusion criteria
* Patients with type 1 diabetes * Patients with very poorly controlled diabetes * Any clinically significant illness, which in the judgement of the investigator would compromise the patient's safety or successful participation in the clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c Levels | Baseline to Week 24 | To compare the change from baseline in HbA1c after 24 weeks treatment (LOCF) between dapagliflozin and placebo in patients with type 2 diabetes who are inadequately controlled on sitagliptin alone or on sitagliptin plus metformin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Mean Change in HbA1c in Participants With Baseline HbA1c ≥8% | Baseline to Week 24 | To compare the change in HbA1c in participants with baseline HbA1c ≥8% achieved with dapagliflozin versus placebo from baseline to week 24. |
| Adjusted Mean Change in Fasting Plasma Glucose (FPG) | Baseline to Week 24 | To compare the change in FPG achieved with dapagliflozin versus placebo from baseline to week 24. |
| Adjusted Mean Change in Body Weight | Baseline to Week 24 | To compare the change in total body weight achieved with dapagliflozin versus placebo from baseline to week 24. |
| Adjusted Mean Change in 2-hour Post Liquid Meal Glucose Rise | Baseline to Week 24 | To compare the change in 2-hour post liquid meal glucose rise achieved with dapagliflozin versus placebo from baseline to week 24. |
| Proportion of Participants Achieving a Therapeutic Glycemic Response Defined as a Reduction in HbA1c of ≥0.7% Compared to Baseline | Baseline to Week 24 | To compare the proportion of participants achieving a therapeutic glycaemic response, defined as a reduction in HbA1c of ≥0.7% compared to baseline, with dapagliflozin versus placebo at week 24. Least Squares Mean represents the percent of participants adjusted for HbA1c baseline value. |
| Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) in Participants With Baseline SBP>=130 mmHg | Baseline to Week 8 | To compare the change in seated systolic blood pressure (SBP) in participants with baseline seated SBP \>=130 achieved with dapagliflozin versus placebo from baseline to week 8. |
Countries
Argentina, Germany, Mexico, Poland, United Kingdom, United States
Participant flow
Recruitment details
First participant enrolled: 10 Oct 2009. Last participant last visit for 24-week period: 10 Mar 2011. 833 participants were enrolled, 452 randomized and 451 treated in 3 European countries, USA, Argentina and Mexico. Participants with T2DM who showed inadequate glycemic control (7.0% ≤ HbA1c ≤ 10.0% at randomization) on sitagliptin +/- metformin.
Pre-assignment details
During a placebo lead-in period, participants were counselled on dietary and life-style modifications. Participants eligible for the study were stratified according to use of metformin.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo plus sitagliptin alone or in combination with metformin | 224 |
| Dapagliflozin Dapagliflozin 10 mg plus sitagliptin alone or in combination with metformin | 223 |
| Total | 447 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 7 |
| Overall Study | Death | 1 | 0 |
| Overall Study | lack of efficacy and subject compliance | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Poor/non-compliance | 0 | 1 |
| Overall Study | site closing | 1 | 0 |
| Overall Study | Subject no longer meets study criteria | 1 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 4 |
Baseline characteristics
| Characteristic | Dapagliflozin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.8 Years STANDARD_DEVIATION 10.42 | 55.0 Years STANDARD_DEVIATION 10.2 | 54.9 Years STANDARD_DEVIATION 10.3 |
| Body weight | 91.02 kg STANDARD_DEVIATION 21.637 | 89.23 kg STANDARD_DEVIATION 20.887 | 90.12 kg STANDARD_DEVIATION 21.259 |
| FPG | 162.19 mg/dL STANDARD_DEVIATION 36.825 | 162.97 mg/dL STANDARD_DEVIATION 34.452 | 162.58 mg/dL STANDARD_DEVIATION 35.618 |
| HbA1c | 7.90 HbA1c [%] STANDARD_DEVIATION 0.806 | 7.97 HbA1c [%] STANDARD_DEVIATION 0.778 | 7.93 HbA1c [%] STANDARD_DEVIATION 0.792 |
| Seated SBP in subjects with baseline seated SBP ≥130 mmHg | 140.46 mmHg STANDARD_DEVIATION 8.018 | 139.30 mmHg STANDARD_DEVIATION 8.507 | 139.85 mmHg STANDARD_DEVIATION 8.279 |
| Sex: Female, Male Female | 96 Participants | 106 Participants | 202 Participants |
| Sex: Female, Male Male | 127 Participants | 118 Participants | 245 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 226 | 9 / 225 |
| serious Total, serious adverse events | 9 / 226 | 10 / 225 |
Outcome results
Primary
Adjusted Mean Change in HbA1c Levels
To compare the change from baseline in HbA1c after 24 weeks treatment (LOCF) between dapagliflozin and placebo in patients with type 2 diabetes who are inadequately controlled on sitagliptin alone or on sitagliptin plus metformin.
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 |
|---|---|---|---|
| Placebo | Adjusted Mean Change in HbA1c Levels | 0.04 Percent | 95% Confidence Interval 0.0509 |
| Dapagliflozin | Adjusted Mean Change in HbA1c Levels | -0.45 Percent | 95% Confidence Interval 0.0509 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin groupp-value: <0.000195% CI: [-0.62, -0.34]ANCOVA
Secondary
Adjusted Mean Change in 2-hour Post Liquid Meal Glucose Rise
To compare the change in 2-hour post liquid meal glucose rise achieved with dapagliflozin versus placebo 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 |
|---|---|---|---|
| Placebo | Adjusted Mean Change in 2-hour Post Liquid Meal Glucose Rise | -6.84 mg/dL | 95% Confidence Interval 2.5098 |
| Dapagliflozin | Adjusted Mean Change in 2-hour Post Liquid Meal Glucose Rise | -21.65 mg/dL | 95% Confidence Interval 2.4604 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin group95% CI: [-21.73, -7.9]ANCOVA
Secondary
Adjusted Mean Change in Body Weight
To compare the change in total body weight achieved with dapagliflozin versus placebo 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 |
|---|---|---|---|
| Placebo | Adjusted Mean Change in Body Weight | -0.26 kg | 95% Confidence Interval 0.1741 |
| Dapagliflozin | Adjusted Mean Change in Body Weight | -2.14 kg | 95% Confidence Interval 0.1745 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin groupp-value: <0.000195% CI: [-2.37, -1.4]ANCOVA
Secondary
Adjusted Mean Change in Fasting Plasma Glucose (FPG)
To compare the change in FPG achieved with dapagliflozin versus placebo 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 |
|---|---|---|---|
| Placebo | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | 3.81 mg/dL | 95% Confidence Interval 2.3474 |
| Dapagliflozin | Adjusted Mean Change in Fasting Plasma Glucose (FPG) | -24.11 mg/dL | 95% Confidence Interval 2.3474 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin groupp-value: <0.000195% CI: [-34.45, -21.4]ANCOVA
Secondary
Adjusted Mean Change in HbA1c in Participants With Baseline HbA1c ≥8%
To compare the change in HbA1c in participants with baseline HbA1c ≥8% achieved with dapagliflozin versus placebo from baseline to week 24.
Time frame: Baseline to Week 24
Population: Full analysis set, participants with baseline HbA1c \>=8% and Week 24 (LOCF) value
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change in HbA1c in Participants With Baseline HbA1c ≥8% | 0.03 Percent | 95% Confidence Interval 0.0775 |
| Dapagliflozin | Adjusted Mean Change in HbA1c in Participants With Baseline HbA1c ≥8% | -0.80 Percent | 95% Confidence Interval 0.0797 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin groupp-value: <0.000195% CI: [-1.05, -0.62]ANCOVA
Secondary
Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) in Participants With Baseline SBP>=130 mmHg
To compare the change in seated systolic blood pressure (SBP) in participants with baseline seated SBP \>=130 achieved with dapagliflozin versus placebo from baseline to week 8.
Time frame: Baseline to Week 8
Population: Full analysis set, participants with baseline SBP\>=130mmHg and Week 8 (LOCF) value
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) in Participants With Baseline SBP>=130 mmHg | -5.12 mmHg | 95% Confidence Interval 1.0211 |
| Dapagliflozin | Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) in Participants With Baseline SBP>=130 mmHg | -5.98 mmHg | 95% Confidence Interval 1.0638 |
Comparison: H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0. The study consisted of two strata: sitagliptin monotherapy group and sitagliptin plus metformin groupp-value: 0.558395% CI: [-3.75, 2.03]ANCOVA
Secondary
Proportion of Participants Achieving a Therapeutic Glycemic Response Defined as a Reduction in HbA1c of ≥0.7% Compared to Baseline
To compare the proportion of participants achieving a therapeutic glycaemic response, defined as a reduction in HbA1c of ≥0.7% compared to baseline, with dapagliflozin versus placebo at week 24. Least Squares Mean represents the percent of participants adjusted for HbA1c baseline value.
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 |
|---|---|---|---|
| Placebo | Proportion of Participants Achieving a Therapeutic Glycemic Response Defined as a Reduction in HbA1c of ≥0.7% Compared to Baseline | 16.6 Percentage of participants | 95% Confidence Interval 2.491 |
| Dapagliflozin | Proportion of Participants Achieving a Therapeutic Glycemic Response Defined as a Reduction in HbA1c of ≥0.7% Compared to Baseline | 35.3 Percentage of participants | 95% Confidence Interval 3.083 |
Comparison: H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0.95% CI: [11.1, 26.4]Regression, Logistic