Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, exenatide once weekly, metformin, sulfonylurea, insulin glargine, Amylin, Lilly
Brief summary
The purpose of this study is to compare the effects of 2.0 mg exenatide once weekly and insulin glargine, titrated to glucose targets using the algorithm described by Yki- Järvinen et al.(2007), with respect to glycemic improvements, body weight, fasting lipids, safety, and tolerability.
Interventions
subcutaneous injection, 2.0mcg, once weekly
DRUGInsulin Glargine
subcutaneous injection, variable dose, QD
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
* Has type 2 diabetes and at least 18 years of age at screening. * Hemoglobin A1c (HbA1c) of 7.1% to 11.0%, inclusive, at screening. * Body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive, at screening. * Have a history of stable body weight (not varying by \>5% for at least 3 months prior to screening). * Have been treated with metformin(Met) for at least 3 months and have been taking a stable dose for at least 8 weeks prior to screening OR * Have been treated with metformin(Met) for at least 3 months and have been taking a stable dose for at least 8 weeks prior to screening and have been treated with SU for at least 3 months and have been taking a stable dose of at least an optimally effective dose of brand of SU for 8 weeks prior to screening.
Exclusion criteria
* Have had a clinically significant history of cardiac disease or presence of active cardiac disease within the year prior to inclusion in the study, including myocardial infarction, clinically significant arrhythmia, unstable angina, moderate to severe congestive heart failure, coronary artery bypass surgery, or angioplasty; or is expected to require coronary artery bypass surgery or angioplasty during the course of the study. * Have clinical signs or symptoms of liver disease, acute or chronic hepatitis. * Have a history of renal transplantation or are currently receiving renal dialysis. * Have active or untreated malignancy, or have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for less than 5 years. * Have had greater than three episodes of major hypoglycemia within 6 months prior to screening. * Have any contraindication for the oral antidiabetic agent which they use. * Have a known allergy or hypersensitivity to insulin glargine, exenatide once weekly, or excipients contained in these agents. * Are known to have active proliferative retinopathy. * Have been treated with drugs that promote weight loss (e.g., Xenical® \[orlistat\], Meridia® \[sibutramine\], Acomplia® \[rimonabant\], Acutrim® \[phenylpropanolamine\], or similar over-the-counter medications) within 3 months of screening. * Have been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening: * Insulin * Thiazolidinediones (e.g., Actos® \[pioglitazone\] or Avandia® \[rosiglitazone\]) * Alpha-glucosidase inhibitors (e.g., Glyset® \[miglitol\] or Precose® \[acarbose\]) * Meglitinides (e.g., Prandin® \[repaglinide\] or Starlix® \[nateglinide\]). * Byetta® (exenatide BID formulation) * Dipeptidyl peptidase (DPP)-4 inhibitors (e.g., Januvia™ \[sitagliptin\], Galvus® \[vildagliptin\]) * Symlin® (pramlintide acetate). * Have had an organ transplant. * Have donated blood within 30 days of screening. * Have previously completed or withdrawn from this study or any other study investigating exenatide once weekly. * Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. * Are currently enrolled in any other clinical study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 26 | Baseline, Week 26 | Change in HbA1c from baseline to Week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving HbA1c <=6.5% at Week 26 | Baseline, Week 26 | Percentage of patients achieving HbA1c \<=6.5% at Week 26 (for patients with HbA1c \>6.5% at baseline) |
| Change in Fasting Serum Glucose (FSG) From Baseline to Week 26 | Baseline, Week 26 | Change in FSG (mmol/L) from Baseline to Week 26 |
| Change in Body Weight (BW) From Baseline to Week 26 | Baseline, Week 26 | Change in BW (kg) from Baseline to Week 26 |
| Change in Total Cholesterol From Baseline to Week 26 | Baseline, Week 26 | Change in Total Cholesterol (mmol/L) from Baseline to Week 26 |
| Percentage of Patients Achieving HbA1c <=7.0% at Week 26 | Baseline, Week 26 | Percentage of patients achieving HbA1c \<=7.0% at Week 26 (for patients with HbA1c \>7% at baseline) |
| Ratio of Triglycerides at Week 26 to Baseline | Baseline, Week 26 | Ratio of Triglycerides (measured in mmol/L) at Week 26 to Baseline. Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline. |
| Change in Blood Pressure From Baseline to Week 26 | Baseline, Week 26 | Change in Systolic Blood Pressure (mmHg) and Diastolic Blood Pressure (mmHg) from Baseline to Week 26 |
| Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Baseline to Week 26 | Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose or documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any time a patient felt that he or she was experiencing a sign or symptom of hypoglycemia that was self-treated or resolved on its own and had a blood glucose level \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. |
| Change in High-density Lipoprotein Cholesterol (HDL) From Baseline to Week 26 | Baseline, Week 26 | Change in HDL (mmol/L) from Baseline to Week 26 |
Countries
Australia, Belgium, Czechia, Denmark, France, Germany, Greece, Hungary, Mexico, Netherlands, Puerto Rico, Russia, South Korea, Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly Patients assigned to the Exenatide Once Weekly group received a 2 mg dose of exenatide injected once a week. | 233 |
| Insulin Glargine Patients assigned to the Insulin Glargine group started insulin glargine treatment with 10 units per day, utilizing the INITIATE (Initiate Insulin by Aggressive Titration and Education) dosing and were instructed to adjust insulin doses to achieve a target blood glucose of 4.0-5.5 mmol/L. | 223 |
| Total | 456 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 2 |
| Overall Study | Entry Criteria Not Met | 3 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Physician Decision | 3 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Sponsor Decision | 1 | 2 |
| Overall Study | Subject Decision | 6 | 19 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly | Insulin Glargine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 49 Participants | 56 Participants | 105 Participants |
| Age, Categorical Between 18 and 65 years | 184 Participants | 167 Participants | 351 Participants |
| Age, Continuous | 57.6 years STANDARD_DEVIATION 9.72 | 58.3 years STANDARD_DEVIATION 9.08 | 57.9 years STANDARD_DEVIATION 9.41 |
| Background Oral Antidiabetic Agent (OAD) Metformin (Met) | 164 participants | 157 participants | 321 participants |
| Background Oral Antidiabetic Agent (OAD) Met+Sulfonylurea (SU) | 69 participants | 66 participants | 135 participants |
| Glycosylated hemoglobin (HbA1c) | 8.32 percentage of total hemoglobin STANDARD_DEVIATION 1.094 | 8.29 percentage of total hemoglobin STANDARD_DEVIATION 1.02 | 8.31 percentage of total hemoglobin STANDARD_DEVIATION 1.057 |
| Sex: Female, Male Female | 113 Participants | 100 Participants | 213 Participants |
| Sex: Female, Male Male | 120 Participants | 123 Participants | 243 Participants |
| Weight | 91.22 kg STANDARD_DEVIATION 18.582 | 90.56 kg STANDARD_DEVIATION 16.348 | 90.90 kg STANDARD_DEVIATION 17.509 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 100 / 233 | 52 / 223 |
| serious Total, serious adverse events | 11 / 233 | 10 / 223 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 26
Change in HbA1c from baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population: All randomized patients who had taken at least one dose of study drug. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Week 26 | -1.47 percentage of total hemoglobin | Standard Error 0.05 |
| Insulin Glargine | Change in HbA1c From Baseline to Week 26 | -1.31 percentage of total hemoglobin | Standard Error 0.06 |
Comparison: Mixed-model Repeated Measures (MMRM) Analysis of Covariance (ANCOVA) model includes treatment, baseline HbA1c, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects. Superiority of exenatide once weekly to insulin glargine is concluded if the upper limit of the 95% confidence interval for the treatment difference \[exenatide once weekly-insulin glargine\]\<0; noninferiority is concluded if this upper limit\<0.3%.p-value: 0.01795% CI: [-0.29, -0.03]Mixed Models Analysis
Secondary
Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes
Major hypoglycemia: any episode with symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure with prompt recovery in response to administration of glucagon or glucose or documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) and required the assistance of another person. Minor hypoglycemia: any time a patient felt that he or she was experiencing a sign or symptom of hypoglycemia that was self-treated or resolved on its own and had a blood glucose level \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia.
Time frame: Baseline to Week 26
Population: ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Major Hypoglycemia | 0.00 rate per subject-year | Standard Error 0 |
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Minor Hypoglycemia | 1.14 rate per subject-year | Standard Error 0.184 |
| Insulin Glargine | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Minor Hypoglycemia | 2.66 rate per subject-year | Standard Error 0.284 |
| Insulin Glargine | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Major Hypoglycemia | 0.03 rate per subject-year | Standard Error 0.03 |
| Exenatide Once Weekly No SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Major Hypoglycemia | 0.01 rate per subject-year | Standard Error 0.013 |
| Exenatide Once Weekly No SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Minor Hypoglycemia | 0.10 rate per subject-year | Standard Error 0.037 |
| Insulin Glargine No SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Major Hypoglycemia | 0.01 rate per subject-year | Standard Error 0.013 |
| Insulin Glargine No SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Episodes | Minor Hypoglycemia | 0.63 rate per subject-year | Standard Error 0.091 |
Secondary
Change in Blood Pressure From Baseline to Week 26
Change in Systolic Blood Pressure (mmHg) and Diastolic Blood Pressure (mmHg) from Baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 26 | Systolic Blood Pressure | -3.03 mmHg | Standard Deviation 16.57 |
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 26 | Diastolic Blood Pressure | -1.15 mmHg | Standard Deviation 10.08 |
| Insulin Glargine | Change in Blood Pressure From Baseline to Week 26 | Systolic Blood Pressure | -0.63 mmHg | Standard Deviation 14.88 |
| Insulin Glargine | Change in Blood Pressure From Baseline to Week 26 | Diastolic Blood Pressure | -0.72 mmHg | Standard Deviation 8.73 |
Secondary
Change in Body Weight (BW) From Baseline to Week 26
Change in BW (kg) from Baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight (BW) From Baseline to Week 26 | -2.63 kg | Standard Error 0.2 |
| Insulin Glargine | Change in Body Weight (BW) From Baseline to Week 26 | 1.42 kg | Standard Error 0.2 |
Comparison: MMRM ANCOVA with change in BW as the dependent variable; treatment, baseline BW, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects.p-value: <0.00195% CI: [-4.57, -3.52]Mixed Models Analysis
Secondary
Change in Fasting Serum Glucose (FSG) From Baseline to Week 26
Change in FSG (mmol/L) from Baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Serum Glucose (FSG) From Baseline to Week 26 | -2.13 mmol/L | Standard Error 0.16 |
| Insulin Glargine | Change in Fasting Serum Glucose (FSG) From Baseline to Week 26 | -2.76 mmol/L | Standard Error 0.16 |
Comparison: MMRM ANCOVA with change in FSG as the dependent variable; treatment, baseline FSG, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects.p-value: 0.00195% CI: [0.25, 1]Mixed Models Analysis
Secondary
Change in High-density Lipoprotein Cholesterol (HDL) From Baseline to Week 26
Change in HDL (mmol/L) from Baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-density Lipoprotein Cholesterol (HDL) From Baseline to Week 26 | -0.00 mmol/L | Standard Error 0.01 |
| Insulin Glargine | Change in High-density Lipoprotein Cholesterol (HDL) From Baseline to Week 26 | 0.01 mmol/L | Standard Error 0.01 |
Comparison: MMRM ANCOVA with change in HDL as the dependent variable; treatment, baseline HDL, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects.p-value: 0.37795% CI: [-0.05, 0.02]Mixed Models Analysis
Secondary
Change in Total Cholesterol From Baseline to Week 26
Change in Total Cholesterol (mmol/L) from Baseline to Week 26
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Week 26 | -0.12 mmol/L | Standard Error 0.06 |
| Insulin Glargine | Change in Total Cholesterol From Baseline to Week 26 | -0.04 mmol/L | Standard Error 0.06 |
Comparison: MMRM ANCOVA with change in total cholesterol as the dependent variable; treatment, baseline total cholesterol, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects.p-value: 0.29295% CI: [-0.21, 0.06]Mixed Models Analysis
Secondary
Percentage of Patients Achieving HbA1c <=6.5% at Week 26
Percentage of patients achieving HbA1c \<=6.5% at Week 26 (for patients with HbA1c \>6.5% at baseline)
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with baseline HbA1c \> 6.5% were included in calculation. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c <=6.5% at Week 26 | 43.2 percentage of patients |
| Insulin Glargine | Percentage of Patients Achieving HbA1c <=6.5% at Week 26 | 28.4 percentage of patients |
Comparison: Percentage of patients achieving HbA1c \<=6.5% at Week 26 were compared between treatments using a CMH test, in which background OAD and country served as the stratification factors.p-value: 0.002Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Achieving HbA1c <=7.0% at Week 26
Percentage of patients achieving HbA1c \<=7.0% at Week 26 (for patients with HbA1c \>7% at baseline)
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with baseline HbA1c \> 7% were included in calculation. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c <=7.0% at Week 26 | 62.2 percentage of patients |
| Insulin Glargine | Percentage of Patients Achieving HbA1c <=7.0% at Week 26 | 54.1 percentage of patients |
Comparison: Percentage of patients achieving HbA1c \<=7.0% at Week 26 were compared between treatments using a Cochran-Mantel-Haenszel (CMH) test, in which background OAD and country served as the stratification factors.p-value: 0.097Cochran-Mantel-Haenszel
Secondary
Ratio of Triglycerides at Week 26 to Baseline
Ratio of Triglycerides (measured in mmol/L) at Week 26 to Baseline. Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with non-missing baseline value and at least one non-missing post-baseline value of the response variable were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Ratio of Triglycerides at Week 26 to Baseline | 0.96 ratio | Standard Error 0.03 |
| Insulin Glargine | Ratio of Triglycerides at Week 26 to Baseline | 0.89 ratio | Standard Error 0.03 |
Comparison: Triglycerides data were logarithm-transformed and the change at Week 26 to baseline, expressed as the ratio, was analyzed by MMRM ANCOVA with change in triglycerides as the dependent variable; treatment, baseline triglycerides, country, background OAD stratum, week of visit, and treatment-by-week interaction as fixed effects; patient and error as random effects.p-value: 0.07795% CI: [0.99, 1.15]Mixed Models Analysis