Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Exenatide, Diabetes drug, Treatment efficacy, Placebo, Metabolism, Cardiovascilar metabolic
Brief summary
Study D5553C00002 is a multicenter, randomized, double-blind, placebo-controlled, parallel group, Phase 3 study to compare the safety and efficacy of exenatide once weekly (EQW) added to titrated basal insulin glargine with or without metformin to placebo added to titrated basal insulin glargine with or without metformin in patients with type 2 diabetes mellitus (T2DM). Eligible patients will be randomized at Visit 5 (Day 1) to receive either EQW added to titrated basal insulin glargine, with or without metformin ≥1500 mg/day, or placebo added to titrated basal insulin glargine, with or without metformin ≥1500 mg/day, during the 28-week treatment period.
Interventions
DRUGExenatide
2 mg weekly suspension injection
Once weekly Placebo injection
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 Type 2 Diabetes Mellitus (T2DM) * Has HbA1c of 7.5% to 12.0%, inclusive, at Visit 1 (Screening). * Has fasting plasma glucose (FPG) concentration \<280 mg/dL (15.6 mmol/L) at Visit 1 (Screening) * Treated with basal insulin glargine at a dose of ≥20 units/day once daily for at least 6 weeks prior to Screening, in combination with diet and exercise alone or in combination with: 1. a stable dose of metformin (≥1500 mg/day) for at least 8 weeks prior to Visit 1 2. a stable dose of metformin (≥1500 mg/day) for at least 8 weeks prior to Visit 1 (Screening) and a stable dose of sulfonylurea for at least 8 weeks prior to the Screening visit
Exclusion criteria
* Serum calcitonin concentration ≥40 pg/mL (≥40 ng/L) at Visit 1 (Screening) * History of, or currently have, acute or chronic pancreatitis, or have triglyceride concentrations ≥500 mg/dL (≥5.65 mmol/L) at Visit 1 * Positive serological test for hepatitis B or hepatitis C
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 in HbA1c achieved with exenatide once weekly (EQW) added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. SU= sulfonylurea. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test (MTT) | Baseline to Week 28 | To compare the change from baseline in 2-hour postprandial glucose after a standard MTT achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. |
| Percentage of Participants Achieving HbA1c <7.0% at Week 28 | Baseline to Week 28 | To compare the percentage of participants achieving HbA1c \<7.0% between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. |
| Change in Body Weight From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline in body weight achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. |
| Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks | Baseline to Week 28 | To compare the percentage of participants achieving HbA1c \<7.0% at Week 28, no weight gain at Week 28, and no major hypoglycemia over 28 weeks between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin. |
| Change in Seated Systolic Blood Pressure From Baseline to Week 28 | Baseline to Week 28 | To compare the change from baseline in seated systolic blood pressure achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. |
| Change From Baseline to Week 28 in Daily Insulin Dose | Baseline to Week 28 | To compare the change from baseline in daily insulin dose achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. |
Countries
Hungary, Poland, Romania, Slovakia, South Africa, United States
Participant flow
Recruitment details
This study was conducted in 107 centers globally between 06 September 2014 and 29 August 2016.
Pre-assignment details
The study had a Screening Visit, an 8-week insulin dose optimization phase, followed by a 28-week randomized, double-blind treatment phase. A total of 464 participants were randomized and entered the double-blind Treatment Period. Of which, 3 participants from 1 center in the United States have been excluded from analyses.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Exenatide 2 mg 1 time per week + titrated basal insulin glargine with or without metformin. | 230 |
| Placebo Placebo (matching with exenatide) 1 time per week + titrated basal insulin glargine with or without metformin. | 228 |
| Total | 458 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 4 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Did not receive treatment | 1 | 0 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Other | 3 | 8 |
| Overall Study | Withdrawal by Subject | 4 | 6 |
Baseline characteristics
| Characteristic | Placebo | Total | Exenatide |
|---|---|---|---|
| Age, Continuous | 57.5 Years STANDARD_DEVIATION 10.28 | 57.7 Years STANDARD_DEVIATION 9.67 | 57.8 Years STANDARD_DEVIATION 9.04 |
| Race/Ethnicity, Customized American Indian Or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Black Or African American | 28 Participants | 47 Participants | 19 Participants |
| Race/Ethnicity, Customized Native Hawaiian Or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 194 Participants | 398 Participants | 204 Participants |
| Sex: Female, Male Female | 122 Participants | 239 Participants | 117 Participants |
| Sex: Female, Male Male | 106 Participants | 219 Participants | 113 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 231 | 1 / 229 |
| other Total, other adverse events | 40 / 231 | 36 / 229 |
| serious Total, serious adverse events | 11 / 231 | 11 / 229 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 28
To compare the change from baseline in HbA1c achieved with exenatide once weekly (EQW) added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. SU= sulfonylurea.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Exenatide | Change in HbA1c From Baseline to Week 28 | -0.96 Percentage of HbA1c |
| Placebo | Change in HbA1c From Baseline to Week 28 | -0.22 Percentage of HbA1c |
p-value: <0.00195% CI: [-0.94, -0.54]Mixed Models Analysis
Secondary
Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test (MTT)
To compare the change from baseline in 2-hour postprandial glucose after a standard MTT achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Exenatide | Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test (MTT) | -28.73 milligram per deciliter |
| Placebo | Change From Baseline to Week 28 in 2-hour Postprandial Glucose After a Standard Meal Tolerance Test (MTT) | -0.96 milligram per deciliter |
p-value: <0.00195% CI: [-39.07, -16.45]ANCOVA
Secondary
Change From Baseline to Week 28 in Daily Insulin Dose
To compare the change from baseline in daily insulin dose achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Exenatide | Change From Baseline to Week 28 in Daily Insulin Dose | 1.6 Units |
| Placebo | Change From Baseline to Week 28 in Daily Insulin Dose | 3.5 Units |
p-value: 0.07495% CI: [-4.1, 0.2]Mixed Models Analysis
Secondary
Change in Body Weight From Baseline to Week 28
To compare the change from baseline in body weight achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Exenatide | Change in Body Weight From Baseline to Week 28 | -1.04 kilogram |
| Placebo | Change in Body Weight From Baseline to Week 28 | 0.48 kilogram |
p-value: <0.00195% CI: [-2.19, -0.85]Mixed Models Analysis
Secondary
Change in Seated Systolic Blood Pressure From Baseline to Week 28
To compare the change from baseline in seated systolic blood pressure achieved with EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment. Only participants with data available for analysis are presented.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Exenatide | Change in Seated Systolic Blood Pressure From Baseline to Week 28 | -2.5 millimeter of mercury |
| Placebo | Change in Seated Systolic Blood Pressure From Baseline to Week 28 | -0.7 millimeter of mercury |
p-value: 0.1195% CI: [-4, 0.4]Mixed Models Analysis
Secondary
Percentage of Participants Achieving HbA1c <7.0% at Week 28
To compare the percentage of participants achieving HbA1c \<7.0% between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Participants Achieving HbA1c <7.0% at Week 28 | 32.6 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% at Week 28 | 7.0 Percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks
To compare the percentage of participants achieving HbA1c \<7.0% at Week 28, no weight gain at Week 28, and no major hypoglycemia over 28 weeks between EQW added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin.
Time frame: Baseline to Week 28
Population: The ITT analysis set included all randomized participants who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks | 22.2 Percentage of participants |
| Placebo | Percentage of Participants Achieving HbA1c <7.0% at Week 28, No Weight Gain at Week 28, and No Major Hypoglycemia Over 28 Weeks | 2.2 Percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel