Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, Byetta, insulin lispro, Humalog, insulin glargine, Lantus, Amylin, Lilly
Brief summary
The study will compare two combination therapies: 1) Combined Basal Insulin Glargine (once a day), Exenatide (twice a day), and Metformin Therapy; or 2) Combined Basal Insulin Glargine (once a day), Bolus Insulin Lispro (three times a day), and Metformin Therapy, in subjects with Type 2 Diabetes Mellitus who have inadequate glycemic control.
Interventions
DRUGexenatide
subcutaneous injection, 5mcg (4 weeks) followed by 10mcg (26 weeks), twice a day
DRUGinsulin lispro
titrated based on pre-meal glucose level; three times a day
DRUGMetformin
DRUGInsulin/ Glargine
Sponsors
Eli Lilly and Company
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
* Have been taking a basal insulin Glargine, at dose of ≥ 20 units/day, for at least 3 months prior to study start. * Have been taking basal insulin Glargine at dose of ≥ 20 units/day, in combination with 1 of the following oral antidiabetic medication (OAM) regimens, for at least 3 months prior to study start: * Metformin or immediate-release metformin or extended-release metformin alone at a maximum tolerated and stable dose with no less than 500 mg/day for at least 6 weeks prior to study start; or * Metformin or immediate-release metformin or extended-release metformin at a maximum tolerated and stable dose with no less than 500 mg/day for at least 6 weeks prior to study start and sulfonylurea at a stable dose for 6 weeks prior to study start. * Have an HbA1C \> 7.0% and ≤ 10.0%. * Have a body mass index (BMI) between ≥ 25 and ≤ 45 kg/m2.
Exclusion criteria
* Are currently taking OAM that is not described above and not allowed with concurrent use of insulin per local product label. * Have taken more than 1 week within 1 month prior to the study start any glucose-lowering medications not included above either alone or in combination formulations, or have used a drug for weight loss (for example, prescription drugs such as orlistat, sibutramine, phenylpropanolamine, rimonabant or similar over-the-counter medications). * Have taken any insulin other than Glargine within the 3 months prior to study start for more than 1 week. * Are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical, intraocular, and inhaled preparations) within 4 weeks prior to the study start. * Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. * Have previously completed or been withdrawn from this study after enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 30 | Baseline, 30 weeks | Change in HbA1c from baseline following 30 weeks of therapy (i.e. HbA1c at week 30 minus HbA1c at baseline). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants Achieving HbA1c ≤ 6.5%. | Week 30 | Percent of participants achieving HbA1c ≤ 6.5%. |
| Change in Fasting Blood Glucose (FBG) From Baseline to Week 30. | Baseline, Week 30 | Change in fasting blood glucose (FBG) from Baseline to Week 30 using MMRM model. The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. |
| Change in Total Cholesterol From Baseline to Week 30 | Baseline, week 30 | Change in total cholesterol from baseline to Week 30 using ANCOVA model. The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. |
| Change in High Density Lipoprotein (HDL) From Baseline to Week 30 | Baseline, week 30 | Change in High Density Lipoprotein (HDL) from baseline to Week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. |
| Change in Low Density Lipoprotein (LDL) From Baseline to Week 30 | Baseline, Week 30 | Change in Low Density Lipoprotein (LDL) from baseline to week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate. |
| Percentage of Participants Achieving HbA1C < 7.0% | Week 30 | Percentage of participants achieving HbA1C \< 7.0% |
| Change in Systolic Blood Pressure (SBP) From Baseline to Week 30 | Baseline, Week 30 | Change in Systolic Blood Pressure (SBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. |
| Change in Diastolic Blood Pressure (DBP) From Baseline to Week 30 | baseline, Week 30 | Change in Diastolic Blood Pressure (DBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. |
| Daily Insulin Glargine Dose at Baseline and at Week 30 | Baseline, week 30 | Daily Insulin Glargine Dose at baseline and at Week 30 |
| Major Hypoglycemia Rate Per Year | 30 weeks | Mean (standard deviation) of major hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Major hypoglycemia was defined as any symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure that shows prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and requiring the assistance of another person because of severe impairment in consciousness or behavior. |
| Minor Hypoglycemia Rate Per Year | 30 weeks | Mean (standard deviation) of minor hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Minor hypoglycemia was defined as any time a participant feels that he or she is experiencing a sign or symptom associated with hypoglycemia that is either self-treated by the participant or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) |
| Change in Body Weight From Baseline to Week 30. | baseline, week 30 | Change in body weight from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects. |
Countries
Argentina, Belgium, Estonia, Finland, France, Germany, Greece, Italy, Mexico, Netherlands, Portugal, Puerto Rico, Romania, Russia, South Korea, Spain, Sweden, United Kingdom
Participant flow
Pre-assignment details
1036 patients entered the study, 637 were assigned to the two interventional study groups. 10 patients assigned to treatment groups did not receive study drug.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide (BET) Basal Insulin/Glargine, Exenatide and Metformin Therapy (BET) | 247 |
| Insulin Lispro (BBT) Basal Insulin/Glargine, Bolus Insulin Lispro and Metformin Therapy (BBT) | 263 |
| Total | 510 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Basal Insulin Optimization Phase (BIO) | Adverse Event | 6 | 0 | 0 |
| Basal Insulin Optimization Phase (BIO) | Entry criteria not met | 331 | 0 | 0 |
| Basal Insulin Optimization Phase (BIO) | Lost to Follow-up | 4 | 0 | 0 |
| Basal Insulin Optimization Phase (BIO) | Physician Decision | 8 | 0 | 0 |
| Basal Insulin Optimization Phase (BIO) | Sponsor decision | 3 | 0 | 0 |
| Basal Insulin Optimization Phase (BIO) | Withdrawal by Subject | 47 | 0 | 0 |
| Interventional Phase | Adverse Event | 0 | 17 | 8 |
| Interventional Phase | Death | 0 | 1 | 0 |
| Interventional Phase | entry criteria not met | 0 | 3 | 0 |
| Interventional Phase | Lack of Efficacy | 0 | 2 | 0 |
| Interventional Phase | Lost to Follow-up | 0 | 0 | 2 |
| Interventional Phase | Physician Decision | 0 | 3 | 5 |
| Interventional Phase | Protocol Violation | 0 | 7 | 2 |
| Interventional Phase | sponsor decision | 0 | 1 | 0 |
| Interventional Phase | Withdrawal by Subject | 0 | 18 | 29 |
Baseline characteristics
| Characteristic | Exenatide (BET) | Insulin Lispro (BBT) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 67 Participants | 81 Participants | 148 Participants |
| Age, Categorical Between 18 and 65 years | 180 Participants | 182 Participants | 362 Participants |
| Age, Continuous | 59.5 years STANDARD_DEVIATION 9.6 | 59.4 years STANDARD_DEVIATION 9.27 | 59.5 years STANDARD_DEVIATION 9.43 |
| Glycosylated hemoglobin (HbA1c) | 8.27 Percent STANDARD_DEVIATION 0.983 | 8.21 Percent STANDARD_DEVIATION 0.871 | 8.24 Percent STANDARD_DEVIATION 0.927 |
| prior use of Sulfonylurea (SU) NO | 162 participants | 164 participants | 326 participants |
| prior use of Sulfonylurea (SU) YES | 85 participants | 99 participants | 184 participants |
| Sex: Female, Male Female | 119 Participants | 130 Participants | 249 Participants |
| Sex: Female, Male Male | 128 Participants | 133 Participants | 261 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 228 / 315 | 175 / 312 |
| serious Total, serious adverse events | 23 / 315 | 26 / 312 |
Outcome results
Primary
Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 30
Change in HbA1c from baseline following 30 weeks of therapy (i.e. HbA1c at week 30 minus HbA1c at baseline).
Time frame: Baseline, 30 weeks
Population: Participants analyzed for this endpoint included the per protocol population, 247 and 263, respectively.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 30 | -1.13 percent of hemoglobin | Standard Error 0.053 |
| Insulin Lispro (BBT) | Change in Glycosylated Hemoglobin (HbA1c) From Baseline to Week 30 | -1.10 percent of hemoglobin | Standard Error 0.051 |
Comparison: The primary objective is to test the hypothesis that BET is non inferior to BBT with respect to change in HbA1c from baseline to Week 30.p-value: 0.627395% CI: [-0.18, 0.11]Mixed model repeated measures
Secondary
Change in Body Weight From Baseline to Week 30.
Change in body weight from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects.
Time frame: baseline, week 30
Population: Participants analyzed were 247 and 263, respectively. These were from the per protocol population (247, 263, respectively) with no missing data (247, 263, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Body Weight From Baseline to Week 30. | -2.45 kg | Standard Error 0.255 |
| Insulin Lispro (BBT) | Change in Body Weight From Baseline to Week 30. | 2.11 kg | Standard Error 0.247 |
Secondary
Change in Diastolic Blood Pressure (DBP) From Baseline to Week 30
Change in Diastolic Blood Pressure (DBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects.
Time frame: baseline, Week 30
Population: Participants included in the analysis = 207 and 227, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (207, 227, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Diastolic Blood Pressure (DBP) From Baseline to Week 30 | -0.64 mmHg | Standard Error 0.594 |
| Insulin Lispro (BBT) | Change in Diastolic Blood Pressure (DBP) From Baseline to Week 30 | -0.14 mmHg | Standard Error 0.572 |
Secondary
Change in Fasting Blood Glucose (FBG) From Baseline to Week 30.
Change in fasting blood glucose (FBG) from Baseline to Week 30 using MMRM model. The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects.
Time frame: Baseline, Week 30
Population: Participants included in the analysis = 243 and 262, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (243, 262, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Fasting Blood Glucose (FBG) From Baseline to Week 30. | -0.46 mmol/L | Standard Error 0.155 |
| Insulin Lispro (BBT) | Change in Fasting Blood Glucose (FBG) From Baseline to Week 30. | 0.18 mmol/L | Standard Error 0.15 |
Secondary
Change in High Density Lipoprotein (HDL) From Baseline to Week 30
Change in High Density Lipoprotein (HDL) from baseline to Week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate.
Time frame: Baseline, week 30
Population: Participants included in the analysis = 237 and 254, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (237, 254, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in High Density Lipoprotein (HDL) From Baseline to Week 30 | -0.04 mmol/L | Standard Error 0.012 |
| Insulin Lispro (BBT) | Change in High Density Lipoprotein (HDL) From Baseline to Week 30 | 0.03 mmol/L | Standard Error 0.012 |
Secondary
Change in Low Density Lipoprotein (LDL) From Baseline to Week 30
Change in Low Density Lipoprotein (LDL) from baseline to week 30 using ANCOVA model.The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate.
Time frame: Baseline, Week 30
Population: Participants included in the analysis = 232 and 245, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (232, 245, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Low Density Lipoprotein (LDL) From Baseline to Week 30 | -0.12 mmol/L | Standard Error 0.042 |
| Insulin Lispro (BBT) | Change in Low Density Lipoprotein (LDL) From Baseline to Week 30 | -0.03 mmol/L | Standard Error 0.042 |
Secondary
Change in Systolic Blood Pressure (SBP) From Baseline to Week 30
Change in Systolic Blood Pressure (SBP) from baseline to Week 30 using MMRM model.The model included the respective baseline outcome as covariate, treatment, country, prior use of SUs, week of visit, and treatment-by-week interaction as fixed effects and patient and error as random effects.
Time frame: Baseline, Week 30
Population: Participants included in the analysis = 207 and 227, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (207, 227, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Systolic Blood Pressure (SBP) From Baseline to Week 30 | -4.13 mmHg | Standard Error 0.952 |
| Insulin Lispro (BBT) | Change in Systolic Blood Pressure (SBP) From Baseline to Week 30 | 0.37 mmHg | Standard Error 0.919 |
Secondary
Change in Total Cholesterol From Baseline to Week 30
Change in total cholesterol from baseline to Week 30 using ANCOVA model. The model included the respective secondary outcome as dependent variable, country, prior use of SU's and treatment groups as factors, and the respective outcomes baseline value as a covariate.
Time frame: Baseline, week 30
Population: Participants included in the analysis = 237 and 254, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (237, 254, respectively).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Change in Total Cholesterol From Baseline to Week 30 | -0.14 mmol/L | Standard Error 0.05 |
| Insulin Lispro (BBT) | Change in Total Cholesterol From Baseline to Week 30 | -0.03 mmol/L | Standard Error 0.049 |
Secondary
Daily Insulin Glargine Dose at Baseline and at Week 30
Daily Insulin Glargine Dose at baseline and at Week 30
Time frame: Baseline, week 30
Population: Participants analyzed were from the per protocol population (247, 263) with no missing data for this endpoint (247, 263, respectively).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide (BET) | Daily Insulin Glargine Dose at Baseline and at Week 30 | Week 30 | 56.9 IU/day | Standard Deviation 29.35 |
| Exenatide (BET) | Daily Insulin Glargine Dose at Baseline and at Week 30 | Baseline | 61.5 IU/day | Standard Deviation 30.94 |
| Insulin Lispro (BBT) | Daily Insulin Glargine Dose at Baseline and at Week 30 | Week 30 | 51.5 IU/day | Standard Deviation 31.44 |
| Insulin Lispro (BBT) | Daily Insulin Glargine Dose at Baseline and at Week 30 | Baseline | 61.1 IU/day | Standard Deviation 35.24 |
Secondary
Major Hypoglycemia Rate Per Year
Mean (standard deviation) of major hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Major hypoglycemia was defined as any symptoms consistent with hypoglycemia resulting in loss of consciousness or seizure that shows prompt recovery in response to administration of glucagon or glucose OR documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and requiring the assistance of another person because of severe impairment in consciousness or behavior.
Time frame: 30 weeks
Population: The As-treated population includes all randomized participants who had taken at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Major Hypoglycemia Rate Per Year | 0.0 rate per year | Standard Deviation 0.23 |
| Insulin Lispro (BBT) | Major Hypoglycemia Rate Per Year | 0.1 rate per year | Standard Deviation 0.39 |
Secondary
Minor Hypoglycemia Rate Per Year
Mean (standard deviation) of minor hyperglycemia episodes experienced per year. Rates per year were calculated for each individual as the number of episodes divided by the total number of days in the study (from randomization to last visit date), then multiplied by 365.25. Minor hypoglycemia was defined as any time a participant feels that he or she is experiencing a sign or symptom associated with hypoglycemia that is either self-treated by the participant or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL)
Time frame: 30 weeks
Population: The As-treated population includes all randomized participants who had taken at least one dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide (BET) | Minor Hypoglycemia Rate Per Year | 2.1 rate per year | Standard Deviation 5.08 |
| Insulin Lispro (BBT) | Minor Hypoglycemia Rate Per Year | 5.0 rate per year | Standard Deviation 12.83 |
Secondary
Percentage of Participants Achieving HbA1C < 7.0%
Percentage of participants achieving HbA1C \< 7.0%
Time frame: Week 30
Population: Participants included in the analysis = 244 and 263, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (244, 263, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide (BET) | Percentage of Participants Achieving HbA1C < 7.0% | 46.7 Percentage of participants |
| Insulin Lispro (BBT) | Percentage of Participants Achieving HbA1C < 7.0% | 42.6 Percentage of participants |
Secondary
Percent of Participants Achieving HbA1c ≤ 6.5%.
Percent of participants achieving HbA1c ≤ 6.5%.
Time frame: Week 30
Population: Participants included in the analysis = 244 and 263, respectively. These numbers derived from the per protocol population (247 and 263, respectively) with no missing data for this endpoint (244, 263, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide (BET) | Percent of Participants Achieving HbA1c ≤ 6.5%. | 26.2 percentage of participants |
| Insulin Lispro (BBT) | Percent of Participants Achieving HbA1c ≤ 6.5%. | 25.5 percentage of participants |