Diabetes Type 2
Conditions
Keywords
Diabetes, Type 2, exenatide, Sitagliptin
Brief summary
To compare the effect on glycemic control (HbA1c) of exenatide suspension administered once weekly to that achieved by sitagliptin or placebo administered once daily for 28 weeks in subjects with type 2 diabetes mellitus.
Interventions
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years old * Diagnosed with type 2 diabetes mellitus * HbA1c of 7.1% to 11.0%, inclusive, at screening * Has stable body weight, i.e., not varying by \>3% for at least 3 months prior to screening * Fasting plasma glucose concentration \<280 mg/dL (15.5 mmol/L) at screening * Body mass index of \<45 kg/m2 at screening * Has been treated with a stable regimen of ≥1500 mg/day metformin for a minimum of 2 months prior to Visit 1 (Screening)
Exclusion criteria
* History of pancreatitis or triglycerides \>=500 mg/dL * Medullary carcinoma or multiple endocrine neoplasia (MEN2) or a family history of either * History of renal transplantation, or is currently receiving renal dialysis, or has an estimated creatinine clearance \<50 mL/min * Active cardiovascular disease * Presence or history of severe congestive heart failure * Central nervous system disease, including epilepsy * Liver disease * History of severe gastrointestinal diseases * Clinically significant malignant disease * Repeated severe hypoglycemia within the last 6 months * Any exposure to exenatide (BYETTA® or BYDUREON™) or any GLP-1 analog * Any DPP-4 inhibitor within 3 months prior screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28 | Baseline to Week 28 | Absolute change in HbA1c from baseline (Day 1, Visit 3) to Week 28/Study Termination (Visit 11). Hypothesis testing on the primary endpoint followed a serial gated procedure with all tests carried out at a 2-sided significance level of 0.05 to protect the family-wise error rate. These tests were conducted sequentially, and are presented in the statistical analysis section below in the order in which they were performed; each test was the gatekeeper of later tests. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline to Week 28 | Percentage of subjects achieving HbA1c target values of \< 7.0% at Week 28/Study Termination. |
| Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28 | Baseline to Week 28 | The change in fasting plasma glucose concentrations from baseline (Day 1) to Week 28/Study Termination. |
| Change in Body Weight (kg) From Baseline to Week 28 | Baseline to Week 28 | The change in body weight (kg) from baseline (Day 1) to Week 28/Study Termination. |
| Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8) | Baseline to Week 16 | The change in 2-hour postprandial plasma glucose from baseline (Day 1) to Visit 8 (Week 16) was analyzed using a general linear model including treatment, and baseline HbA1c stratum (\< 9% or ≥ 9%) as fixed factors, and the baseline 2-hour postprandial plasma glucose concentrations as a covariate. |
Countries
United States
Participant flow
Pre-assignment details
Subjects were randomly assigned across 3 treatment groups (exenatide, sitagliptin, and placebo) in a ratio of 3:2:1, with randomization stratified by screening HbA1c stratum (\< 9% or 9%).
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Exenatide Exenatide once weekly suspension 2mg subcutaneous injection | 181 |
| Active Comparator: Sitagliptin Sitagliptin 100mg oral tablet once daily | 122 |
| Placebo Comparator: Placebo Placebo oral tablet once daily | 61 |
| Total | 364 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Administrative | 1 | 0 | 0 |
| Overall Study | Adverse Event | 4 | 0 | 3 |
| Overall Study | Lost to Follow-up | 6 | 6 | 3 |
| Overall Study | Physician Decision | 1 | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 14 | 7 | 7 |
Baseline characteristics
| Characteristic | Experimental: Exenatide | Active Comparator: Sitagliptin | Placebo Comparator: Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 9.82 | 54.3 Years STANDARD_DEVIATION 9.01 | 53.4 Years STANDARD_DEVIATION 9.48 | 53.7 Years STANDARD_DEVIATION 9.49 |
| Age, Customized <65 years | 154 Participants | 106 Participants | 54 Participants | 314 Participants |
| Age, Customized >=65 years | 27 Participants | 16 Participants | 7 Participants | 50 Participants |
| Baseline HbA1c | 8.42 percentage of total hemoglobin STANDARD_DEVIATION 0.997 | 8.50 percentage of total hemoglobin STANDARD_DEVIATION 1.043 | 8.50 percentage of total hemoglobin STANDARD_DEVIATION 1.043 | 8.46 percentage of total hemoglobin STANDARD_DEVIATION 1.018 |
| Fasting Plasma Glucose | 178.0 mg/dL STANDARD_DEVIATION 46.64 | 176.9 mg/dL STANDARD_DEVIATION 42.5 | 172.8 mg/dL STANDARD_DEVIATION 44.31 | 176.8 mg/dL STANDARD_DEVIATION 44.82 |
| HbA1c Stratum < 9.0% | 125 participants | 83 participants | 42 participants | 250 participants |
| HbA1c Stratum >= 9.0% | 56 participants | 39 participants | 19 participants | 114 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 2 Participants | 3 Participants | 14 Participants |
| Race/Ethnicity, Customized Black or African American | 24 Participants | 18 Participants | 7 Participants | 49 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 111 Participants | 77 Participants | 32 Participants | 220 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 70 Participants | 45 Participants | 29 Participants | 144 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 148 Participants | 98 Participants | 50 Participants | 296 Participants |
| Sex: Female, Male Female | 92 Participants | 56 Participants | 24 Participants | 172 Participants |
| Sex: Female, Male Male | 89 Participants | 66 Participants | 37 Participants | 192 Participants |
| Weight | 89.15 kg STANDARD_DEVIATION 21.413 | 88.09 kg STANDARD_DEVIATION 20.282 | 88.95 kg STANDARD_DEVIATION 20.136 | 88.76 kg STANDARD_DEVIATION 20.778 |
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 | 31 / 181 | 2 / 122 | 4 / 61 |
| serious Total, serious adverse events | 5 / 181 | 0 / 122 | 2 / 61 |
Outcome results
Primary
Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28
Absolute change in HbA1c from baseline (Day 1, Visit 3) to Week 28/Study Termination (Visit 11). Hypothesis testing on the primary endpoint followed a serial gated procedure with all tests carried out at a 2-sided significance level of 0.05 to protect the family-wise error rate. These tests were conducted sequentially, and are presented in the statistical analysis section below in the order in which they were performed; each test was the gatekeeper of later tests.
Time frame: Baseline to Week 28
Population: Modified Intent-to-Treat: Subjects who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Exenatide | Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28 | -1.13 percentage of total hemoglobin | Standard Error 0.1093 |
| Active Comparator: Sitagliptin | Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28 | -0.75 percentage of total hemoglobin | Standard Error 0.1324 |
| Placebo Comparator: Placebo | Change in HbA1c (Glycosylated Hemoglobin) From Baseline to Week 28 | -0.40 percentage of total hemoglobin | Standard Error 0.1945 |
p-value: 0.00195% CI: [-1.15, -0.3]mixed model for repeated measure
p-value: 0.020995% CI: [-0.7, -0.06]mixed model for repeated measure
p-value: 0.134795% CI: [-0.79, 0.11]mixed model for repeated measure
Secondary
Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8)
The change in 2-hour postprandial plasma glucose from baseline (Day 1) to Visit 8 (Week 16) was analyzed using a general linear model including treatment, and baseline HbA1c stratum (\< 9% or ≥ 9%) as fixed factors, and the baseline 2-hour postprandial plasma glucose concentrations as a covariate.
Time frame: Baseline to Week 16
Population: Meal Test Evaluable Population: The Meal Test Evaluable Population consists of all modified ITT subjects who participated in the meal test, consumed at least 75% of the standardized meal and had no missing 2-hour postprandial glucose measurements at both Visit 3 (Day 1) and Visit 8 (Week 16), and have adequate study drug exposure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Exenatide | Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8) | -59.57 mg/dL | Standard Error 10.48 |
| Active Comparator: Sitagliptin | Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8) | -23.61 mg/dL | Standard Error 13.04 |
| Placebo Comparator: Placebo | Change in 2-hour Postprandial Glucose Concentrations From Baseline to Week 16 (Visit 8) | -38.68 mg/dL | Standard Error 16.98 |
p-value: 0.024895% CI: [-67.23, -4.68]general linear model
p-value: 0.291495% CI: [-60.02, 18.25]general linear model
Secondary
Change in Body Weight (kg) From Baseline to Week 28
The change in body weight (kg) from baseline (Day 1) to Week 28/Study Termination.
Time frame: Baseline to Week 28
Population: Modified Intent-to-Treat: Subjects who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Exenatide | Change in Body Weight (kg) From Baseline to Week 28 | -1.12 kg | Standard Error 0.2592 |
| Active Comparator: Sitagliptin | Change in Body Weight (kg) From Baseline to Week 28 | -1.19 kg | Standard Error 0.3134 |
| Placebo Comparator: Placebo | Change in Body Weight (kg) From Baseline to Week 28 | 0.15 kg | Standard Error 0.4767 |
p-value: 0.862595% CI: [-0.73, 0.87]mixed model for repeated measure
p-value: 0.019895% CI: [-2.34, -0.2]mixed model for repeated measure
Secondary
Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28
The change in fasting plasma glucose concentrations from baseline (Day 1) to Week 28/Study Termination.
Time frame: Baseline to Week 28
Population: Modified Intent-to-Treat: Subjects who were randomized and received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Exenatide | Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28 | -21.3 mg/dL | Standard Error 3.864 |
| Active Comparator: Sitagliptin | Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28 | -11.3 mg/dL | Standard Error 4.617 |
| Placebo Comparator: Placebo | Change in Fasting Plasma Glucose Concentrations From Baseline to Week 28 | 9.6 mg/dL | Standard Error 7.097 |
p-value: 0.092495% CI: [-21.8, 1.7]mixed model for repeated measure
p-value: 0.000195% CI: [-46.7, -15.1]mixed model for repeated measure
Secondary
Percentage of Subjects Achieving HbA1c <7% at Week 28
Percentage of subjects achieving HbA1c target values of \< 7.0% at Week 28/Study Termination.
Time frame: Baseline to Week 28
Population: Modified Intent-to-Treat: Subjects who were randomized and received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Exenatide | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline No | 96.7 percentage of subjects |
| Experimental: Exenatide | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline Yes | 3.3 percentage of subjects |
| Experimental: Exenatide | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 Yes | 43.1 percentage of subjects |
| Experimental: Exenatide | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 No | 56.9 percentage of subjects |
| Active Comparator: Sitagliptin | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 No | 68.0 percentage of subjects |
| Active Comparator: Sitagliptin | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 Yes | 32.0 percentage of subjects |
| Active Comparator: Sitagliptin | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline Yes | 1.6 percentage of subjects |
| Active Comparator: Sitagliptin | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline No | 98.4 percentage of subjects |
| Placebo Comparator: Placebo | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline Yes | 3.3 percentage of subjects |
| Placebo Comparator: Placebo | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Baseline No | 96.7 percentage of subjects |
| Placebo Comparator: Placebo | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 Yes | 24.6 percentage of subjects |
| Placebo Comparator: Placebo | Percentage of Subjects Achieving HbA1c <7% at Week 28 | Week 28 No | 75.4 percentage of subjects |
Comparison: Percentage of Subjects Achieving HbA1c \<7% at Week 28.p-value: 0.0489Cochran-Mantel-Haenszel
Comparison: Percentage of Subjects Achieving HbA1c \<7% at Week 28.p-value: 0.0103Cochran-Mantel-Haenszel