Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Exenatide, Dapagliflozin, Diabetes medication, Treatment efficacy, Placebo, Metabolism, Cardiovascular metabolic
Brief summary
Study D5553C0003 is a 28-week, randomized, double-blind, active-controlled, multicenter, Phase 3 efficacy and safety study with 24-week and 52-week extension phases of simultaneous administration of exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg once daily (QD) compared to EQW 2 mg alone and dapagliflozin 10 mg QD alone in patients with Type 2 diabetes who have inadequate glycemic control on metformin.
Interventions
DRUGExantide with Dapagliflozin
2 mg weekly suspension injection and 10 mg Dapagliflozin
DRUGExentide
2 mg
DRUGDapagliflozin
10 mg once daily Dapagliflozin
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Has a diagnosis of T2DM. * Has HbA1c of 8.0% to 12.0%, inclusive, at Visit 1 and Visit 2. * Treated with a stable dose of metformin ≥1500 mg/day for at least 2 months prior to Screening.
Exclusion criteria
* FPG ≥280 mg/dL (15.6 mmol/L). * Serum calcitonin concentration ≥40 pg/mL (≥40 ng/L) at Visit 1 (Screening) * Clinically significant abnormal free T4 values or patients needing initiation or adjustment of thyroid treatment according to the investigator. * Abnormal thyroid stimulating hormone (TSH) value at Screening will be further evaluated by free T4.Patients with clinically significant abnormal free T4 values will be excluded. * Known active proliferative retinopathy. * History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥500 mg/dL (≥5.65 mmol/L) at Visit 1 * History or presence of inflammatory bowel disease or other severe GI diseases, particularly those which may impact gastric emptying, such as gastroparesis or pyloric stenosis. * History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study. Current use of gastric balloons is also excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline to Week 28 in HbA1c between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Plasma Glucose From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline to Week 28 in fasting plasma glucose between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test | Baseline to Week 28 | To compare the change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Percentage of Patients Achieving Weight Loss ≥5.0% at Week 28 | Baseline to Week 28 | To compare the percentage of patients achieving weight loss ≥5.0% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Change in Body Weight From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline to Week 28 in body weight between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Percentage of Patients Achieving HbA1c <7% at Week 28 | Baseline to Week 28 | To compare the percentage of patients achieving HbA1c \<7% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Change in Systolic Blood Pressure From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline to Week 28 in systolic blood pressure between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
| Change in Fasting Plasma Glucose From Baseline to Week 2 | Baseline to Week 2 | To compare the change from baseline to Week 2 in fasting plasma glucose between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. |
Countries
Hungary, Poland, Romania, Slovakia, South Africa, United States
Participant flow
Recruitment details
Study conducted between 04 September 2014 and 28 December 2017. 118 centers in 6 countries randomized patients in the study. A Primary Analysis was performed following completion of the 28-week Treatment Period with a data cut-off date of 26 April 2016. All Primary and Secondary Outcome measures were reported at the time of the Primary Analysis.
Pre-assignment details
The study had a Screening Visit, a 1-week placebo Lead-in Period, a Randomization Visit, and 9 further visits at 1- to 4-week intervals during a 28-week Treatment Period. Patients then entered a 24-week Extension Period 1 and subsequent 52-week Extension Period 2. A follow-up visit occurred 10 weeks after last dose of study medication.
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin + Placebo Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry. | 230 |
| Exenatide + Dapagliflozin Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry. | 228 |
| Exenatide + Placebo Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry. | 227 |
| Total | 685 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 12 | 12 |
| Overall Study | Death | 2 | 3 | 1 |
| Overall Study | Lost to Follow-up | 14 | 14 | 21 |
| Overall Study | Other | 10 | 18 | 15 |
| Overall Study | Patient Incorrectly Randomized | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 1 | 0 |
| Overall Study | Study-Specific Withdrawal Criteria | 0 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 42 | 28 | 41 |
| Overall Study | Withdrew; No Record on Termination Page | 2 | 0 | 1 |
Baseline characteristics
| Characteristic | Exenatide + Dapagliflozin | Exenatide + Placebo | Total | Dapagliflozin + Placebo |
|---|---|---|---|---|
| Age, Continuous | 53.8 Years STANDARD_DEVIATION 9.82 | 54.2 Years STANDARD_DEVIATION 9.62 | 54.2 Years STANDARD_DEVIATION 9.53 | 54.5 Years STANDARD_DEVIATION 9.16 |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Black Or African American | 34 Participants | 27 Participants | 94 Participants | 33 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 3 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 190 Participants | 194 Participants | 573 Participants | 189 Participants |
| Sex: Female, Male Female | 126 Participants | 111 Participants | 357 Participants | 120 Participants |
| Sex: Female, Male Male | 102 Participants | 116 Participants | 328 Participants | 110 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 233 | 3 / 231 | 1 / 230 |
| other Total, other adverse events | 73 / 233 | 87 / 231 | 78 / 230 |
| serious Total, serious adverse events | 18 / 233 | 17 / 231 | 18 / 230 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 28
To compare the change from baseline to Week 28 in HbA1c between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change in HbA1c From Baseline to Week 28 | -1.39 % HbA1c |
| Exenatide + Dapagliflozin | Change in HbA1c From Baseline to Week 28 | -1.98 % HbA1c |
| Exenatide + Placebo | Change in HbA1c From Baseline to Week 28 | -1.60 % HbA1c |
p-value: 0.00395% CI: [-0.63, -0.13]Mixed Models Analysis
p-value: <0.00195% CI: [-0.84, -0.34]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test
To compare the change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test | -61.05 mg/dL |
| Exenatide + Dapagliflozin | Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test | -87.83 mg/dL |
| Exenatide + Placebo | Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test | -60.09 mg/dL |
p-value: <0.00195% CI: [-37.89, -17.59]ANCOVA
p-value: <0.00195% CI: [-36.78, -16.78]ANCOVA
Secondary
Change in Body Weight From Baseline to Week 28
To compare the change from baseline to Week 28 in body weight between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change in Body Weight From Baseline to Week 28 | -2.22 kilogram |
| Exenatide + Dapagliflozin | Change in Body Weight From Baseline to Week 28 | -3.55 kilogram |
| Exenatide + Placebo | Change in Body Weight From Baseline to Week 28 | -1.56 kilogram |
p-value: <0.00195% CI: [-2.79, -1.2]Mixed Models Analysis
p-value: <0.00195% CI: [-2.12, -0.55]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose From Baseline to Week 2
To compare the change from baseline to Week 2 in fasting plasma glucose between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 2
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change in Fasting Plasma Glucose From Baseline to Week 2 | -26.31 mg/dL |
| Exenatide + Dapagliflozin | Change in Fasting Plasma Glucose From Baseline to Week 2 | -41.34 mg/dL |
| Exenatide + Placebo | Change in Fasting Plasma Glucose From Baseline to Week 2 | -21.08 mg/dL |
p-value: <0.00195% CI: [-27.12, -13.4]Mixed Models Analysis
p-value: <0.00195% CI: [-21.85, -8.2]Mixed Models Analysis
Secondary
Change in Fasting Plasma Glucose From Baseline to Week 28
To compare the change from baseline to Week 28 in fasting plasma glucose between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change in Fasting Plasma Glucose From Baseline to Week 28 | -49.19 milligrams/deciliter (mg/dL) |
| Exenatide + Dapagliflozin | Change in Fasting Plasma Glucose From Baseline to Week 28 | -65.83 milligrams/deciliter (mg/dL) |
| Exenatide + Placebo | Change in Fasting Plasma Glucose From Baseline to Week 28 | -45.75 milligrams/deciliter (mg/dL) |
p-value: <0.00195% CI: [-27.95, -12.2]Mixed Models Analysis
p-value: <0.00195% CI: [-24.39, -8.89]Mixed Models Analysis
Secondary
Change in Systolic Blood Pressure From Baseline to Week 28
To compare the change from baseline to Week 28 in systolic blood pressure between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Dapagliflozin + Placebo | Change in Systolic Blood Pressure From Baseline to Week 28 | -1.8 millimeters of mercury (mmHg) |
| Exenatide + Dapagliflozin | Change in Systolic Blood Pressure From Baseline to Week 28 | -4.3 millimeters of mercury (mmHg) |
| Exenatide + Placebo | Change in Systolic Blood Pressure From Baseline to Week 28 | -1.2 millimeters of mercury (mmHg) |
p-value: 0.00595% CI: [-5.2, -0.9]Mixed Models Analysis
p-value: 0.02295% CI: [-4.5, -0.4]Mixed Models Analysis
Secondary
Percentage of Patients Achieving HbA1c <7% at Week 28
To compare the percentage of patients achieving HbA1c \<7% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Placebo | Percentage of Patients Achieving HbA1c <7% at Week 28 | 19.1 % of patients |
| Exenatide + Dapagliflozin | Percentage of Patients Achieving HbA1c <7% at Week 28 | 44.7 % of patients |
| Exenatide + Placebo | Percentage of Patients Achieving HbA1c <7% at Week 28 | 26.9 % of patients |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Achieving Weight Loss ≥5.0% at Week 28
To compare the percentage of patients achieving weight loss ≥5.0% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapagliflozin + Placebo | Percentage of Patients Achieving Weight Loss ≥5.0% at Week 28 | 20.0 % of patients |
| Exenatide + Dapagliflozin | Percentage of Patients Achieving Weight Loss ≥5.0% at Week 28 | 33.3 % of patients |
| Exenatide + Placebo | Percentage of Patients Achieving Weight Loss ≥5.0% at Week 28 | 13.7 % of patients |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: 0.001Cochran-Mantel-Haenszel