Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, overweight, obesity, weight loss, exenatide, Amylin, Lilly
Brief summary
This trial is designed to compare the effects of twice-daily exenatide and twice-daily placebo on weight loss. This trial will evaluate overweight and obese subjects with type 2 diabetes who have inadequate glycemic control with metformin, sulfonylurea, or metformin plus a sulfonylurea. Subjects will be treated with exenatide or placebo in addition to their current oral antidiabetes agent regimen and participate in a lifestyle modification program.
Interventions
DRUGexenatide
subcutaneous injection, 5mcg or 10mcg, twice a day
DRUGplacebo
subcutaneous injection, volume equivalent to exenatide dose, twice a day
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with type 2 diabetes for at least 6 months * Have been treated with a stable dose of the following for at least 6 weeks prior to screening: \*immediate or extended release metformin, or \*a sulfonylurea, or \*a fixed-dose sulfonylurea/metformin combination therapy * Have an HbA1c of 6.6% to 10.0%, inclusive * Have a Body Mass Index (BMI) of 25 kg/m\^2 to 39.9 kg/m\^2, inclusive
Exclusion criteria
* Are treated with any of the following excluded medications: \*exogenous insulin, thiazolidinedione, or alpha-glucosidase inhibitor for more than 1 week within 6 weeks of screening; \*Symlin injection at any time; \* Byetta injection within 3 months of screening or discontinuation of therapy at any time due to adverse reaction; \*drugs that directly affect gastrointestinal motility; \*use of a weight loss drug (including those available over the counter) within 3 months of screening; \*chronic (lasting longer than 2 weeks) systemic corticosteroids (excluding topical, intranasal, and inhaled preparations) by oral, intravenous, or intramuscular route within 2 months of screening * Have conditions contraindicating metformin and/or sulfonylurea use * Have had a change in lipid-lowering agents within 6 weeks of screening * Have received glucagon-like peptide-1 (GLP-1) analogs, or dipeptidyl peptidase-IV inhibitors (DPP-IV inhibitors) or have previously participated in this study * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Weight | Baseline, Week 24 | Change in body weight from baseline (Week 0) after 24 weeks of treatment (i.e., weight at week 24 minus weight at week 0). Body weight measured in kilograms (k). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | baseline, Week 24 | Change in SMBG at each of 6 time points throughout a day (blood glucose measurements before and 2 hours after the start of the morning, mid-day, and evening meals); week 24 compared to week 0 (i.e., SMBG at week 24 minus SMBG at week 0). Fasting Glucose measured in millimoles per liter (mmol/L). |
| Change From Baseline in Waist Circumference at Week 24 | baseline, Week 24 | Change in waist circumference from baseline after 24 weeks of treatment (i.e., waist circumference at week 24 minus waist circumference at week 0). Waist measured in centimeters (cm). |
| Ratio of Homeostatic Model Assessment-Beta Cell (HOMA-B) at Week 24 to HOMA-B at Baseline | baseline, Week 24 | Ratio of HOMA-B at Week 24 to HOMA-B at baseline (Week 0). HOMA-B is a computer solved model used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency. HOMA-B allows a quantitative assessment of the contributions of deficient beta cell function to the fasting hyperglycemia. HOMA-B is measured as a percent of the normal population (normal beta cell function = 100%, which is used as a reference in the calculation). The higher the percent the better for the participant. |
| Ratio of Homeostatic Model Assessment-Insulin Sensitivity (HOMA-S) at Week 24 to HOMA-S at Baseline | baseline, Week 24 | Ratio of HOMA-S at Week 24 to HOMA-S at baseline, week 0. HOMA-S is a computer solved model used to predict the homeostatic concentrations which arise from varying degrees of insulin sensitivity. HOMA-S allows a quantitative assessment of the contributions of insulin sensitivity to the fasting hyperglycemia. HOMA-S is measured as a percent of the normal population (normal insulin sensitivity = 100%, which is used as a reference in the calculation). The higher the percent the better for the participant. |
| Change From Baseline in High Density Lipoprotein (HDL) Cholesterol at Week 24 | baseline, Week 24 | Change in HDL cholesterol from baseline after 24 weeks of treatment (i.e., HDL cholesterol at week 24 minus HDL cholesterol at week 0). HDL measured as mmol/L. |
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | baseline, Week 24 | Change in HbA1c from baseline (Week 0) after 24 weeks of treatment (i.e., HbA1c at week 24 minus HbA1c at week 0). HbA1c is measured as percent (%) of hemoglobin. |
| Change From Baseline in Total Cholesterol at Week 24 | baseline, week 24 | Change in total cholesterol from baseline after 24 weeks of treatment (i.e., total cholesterol at week 24 minus total cholesterol at week 0). Total cholesterol measured in mmol/L. |
| Ratio of Triglycerides at Week 24 to Triglycerides at Baseline | baseline, Week 24 | Ratio of triglyceride levels at Week 24 to triglyceride levels at baseline, Week 0 (ie., triglycerides at Week 24 divided by triglycerides at baseline, Week 0). Triglycerides measured in mmol/L. |
| Number of Participants With Hypoglycemic Events During the Study | Baseline to 24 weeks | Number of participants experiencing one or more events of hypoglycemia at any point in the study |
| Rate of Hypoglycemic Events | 24 weeks | Overall rate of hypoglycemia, adjusted for 1 year (ie., events of hypoglycemia per participant per year). |
| Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol at Week 24 | baseline, Week 24 | Change in LDL cholesterol from baseline (Week 0) after 24 weeks of treatment (ie., LDL cholesterol at week 24 minus LDL cholesterol at week 0). LDL cholesterol measured in mmol/L |
Countries
United States
Participant flow
Pre-assignment details
One randomized patient per group discontinued before receiving study drug. These patients are not included in the started category below.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Exenatide) exenatide 5mcg twice daily for 4 weeks, followed by exenatide 10mcg twice daily for 20 weeks | 96 |
| Group B (Placebo) placebo (volume equivalent to exenatide injection) twice daily for 24 weeks | 98 |
| Total | 194 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 |
| Overall Study | Entry Criteria Not Met | 0 | 1 |
| Overall Study | Loss of Glucose Control | 0 | 1 |
| Overall Study | Lost to Follow-up | 10 | 5 |
| Overall Study | Physician Decision | 0 | 4 |
| Overall Study | Protocol Violation | 6 | 3 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Group A (Exenatide) | Group B (Placebo) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 18 Participants | 16 Participants | 34 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 82 Participants | 160 Participants |
| Age, Continuous | 54.52 years STANDARD_DEVIATION 10.02 | 55.08 years STANDARD_DEVIATION 8.97 | 54.81 years STANDARD_DEVIATION 9.48 |
| Baseline Body Weight | 94.90 kg STANDARD_DEVIATION 16.52 | 96.16 kg STANDARD_DEVIATION 16.53 | 95.53 kg STANDARD_DEVIATION 16.05 |
| Baseline Cholesterol | 4.67 mmol/L STANDARD_DEVIATION 1.03 | 4.68 mmol/L STANDARD_DEVIATION 0.9 | 4.68 mmol/L STANDARD_DEVIATION 0.96 |
| Baseline Glycosylated Hemoglobin (HbA1c) | 7.74 percent hemoglobin STANDARD_DEVIATION 0.87 | 7.51 percent hemoglobin STANDARD_DEVIATION 0.82 | 7.62 percent hemoglobin STANDARD_DEVIATION 0.85 |
| Baseline High Density Lipoprotein (HDL) Cholesterol | 1.18 mmol/L STANDARD_DEVIATION 0.32 | 1.21 mmol/L STANDARD_DEVIATION 0.31 | 1.20 mmol/L STANDARD_DEVIATION 0.31 |
| Baseline Homeostatic Model Assessment-Beta Cell (HOMA-B) | 75.15 Percent beta-cell function STANDARD_DEVIATION 81.2 | 70.72 Percent beta-cell function STANDARD_DEVIATION 53.16 | 72.81 Percent beta-cell function STANDARD_DEVIATION 67.65 |
| Baseline Homeostatic Model Assessment-Insulin Sensitivity (HOMA-S) | 49.72 Percent insulin sensitivity STANDARD_DEVIATION 32.12 | 62.90 Percent insulin sensitivity STANDARD_DEVIATION 41.07 | 56.68 Percent insulin sensitivity STANDARD_DEVIATION 37.57 |
| Baseline Low Density Lipoprotein (LDL) Cholesterol | 2.74 mmol/L STANDARD_DEVIATION 0.88 | 2.78 mmol/L STANDARD_DEVIATION 0.82 | 2.76 mmol/L STANDARD_DEVIATION 0.85 |
| Baseline Triglycerides | 2.15 mmol/L STANDARD_DEVIATION 0.94 | 2.13 mmol/L STANDARD_DEVIATION 1 | 2.14 mmol/L STANDARD_DEVIATION 0.97 |
| Baseline Waist Circumference | 109.64 cm STANDARD_DEVIATION 11.12 | 108.85 cm STANDARD_DEVIATION 12.1 | 109.24 cm STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 60 Participants | 61 Participants | 121 Participants |
| Sex: Female, Male Male | 36 Participants | 37 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 87 / — | 82 / — |
| serious Total, serious adverse events | 2 / — | 2 / — |
Outcome results
Primary
Change From Baseline in Body Weight
Change in body weight from baseline (Week 0) after 24 weeks of treatment (i.e., weight at week 24 minus weight at week 0). Body weight measured in kilograms (k).
Time frame: Baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in Body Weight | -6.16 kg | Standard Error 0.54 |
| Group B (Placebo) | Change From Baseline in Body Weight | -3.97 kg | Standard Error 0.52 |
p-value: 0.003Mixed Model Repeated Measures
Secondary
Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24
Change in SMBG at each of 6 time points throughout a day (blood glucose measurements before and 2 hours after the start of the morning, mid-day, and evening meals); week 24 compared to week 0 (i.e., SMBG at week 24 minus SMBG at week 0). Fasting Glucose measured in millimoles per liter (mmol/L).
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Morning Pre-Meal | -1.87 mmol/L | Standard Error 0.17 |
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Morning Meal | -2.67 mmol/L | Standard Error 0.22 |
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Midday Pre-Meal | -1.40 mmol/L | Standard Error 0.19 |
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Midday Meal | -2.12 mmol/L | Standard Error 0.21 |
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Evening Pre-Meal | -1.57 mmol/L | Standard Error 0.19 |
| Group A (Exenatide) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Evening Meal | -3.09 mmol/L | Standard Error 0.22 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Evening Pre-Meal | -1.32 mmol/L | Standard Error 0.19 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Morning Pre-Meal | -1.20 mmol/L | Standard Error 0.17 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Midday Meal | -1.51 mmol/L | Standard Error 0.2 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Morning Meal | -1.92 mmol/L | Standard Error 0.22 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | 2 Hours Post Evening Meal | -2.28 mmol/L | Standard Error 0.23 |
| Group B (Placebo) | Change From Baseline in 6-point Self Monitored Blood Glucose (SMBG) Profile at Week 24 | Midday Pre-Meal | -1.37 mmol/L | Standard Error 0.19 |
Secondary
Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24
Change in HbA1c from baseline (Week 0) after 24 weeks of treatment (i.e., HbA1c at week 24 minus HbA1c at week 0). HbA1c is measured as percent (%) of hemoglobin.
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -1.21 percent hemoglobin | Standard Error 0.09 |
| Group B (Placebo) | Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Week 24 | -0.73 percent hemoglobin | Standard Error 0.09 |
p-value: <0.0001Mixed Model Repeated Measures
Secondary
Change From Baseline in High Density Lipoprotein (HDL) Cholesterol at Week 24
Change in HDL cholesterol from baseline after 24 weeks of treatment (i.e., HDL cholesterol at week 24 minus HDL cholesterol at week 0). HDL measured as mmol/L.
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in High Density Lipoprotein (HDL) Cholesterol at Week 24 | 0.02 mmol/L | Standard Error 0.02 |
| Group B (Placebo) | Change From Baseline in High Density Lipoprotein (HDL) Cholesterol at Week 24 | 0.02 mmol/L | Standard Error 0.02 |
p-value: 0.8279ANCOVA
Secondary
Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol at Week 24
Change in LDL cholesterol from baseline (Week 0) after 24 weeks of treatment (ie., LDL cholesterol at week 24 minus LDL cholesterol at week 0). LDL cholesterol measured in mmol/L
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol at Week 24 | -0.06 mmol/L | Standard Error 0.08 |
| Group B (Placebo) | Change From Baseline in Low Density Lipoprotein (LDL) Cholesterol at Week 24 | -0.04 mmol/L | Standard Error 0.07 |
p-value: 0.8334ANCOVA
Secondary
Change From Baseline in Total Cholesterol at Week 24
Change in total cholesterol from baseline after 24 weeks of treatment (i.e., total cholesterol at week 24 minus total cholesterol at week 0). Total cholesterol measured in mmol/L.
Time frame: baseline, week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in Total Cholesterol at Week 24 | -0.16 mmol/L | Standard Error 0.1 |
| Group B (Placebo) | Change From Baseline in Total Cholesterol at Week 24 | -0.03 mmol/L | Standard Error 0.1 |
p-value: 0.2881ANCOVA
Secondary
Change From Baseline in Waist Circumference at Week 24
Change in waist circumference from baseline after 24 weeks of treatment (i.e., waist circumference at week 24 minus waist circumference at week 0). Waist measured in centimeters (cm).
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Change From Baseline in Waist Circumference at Week 24 | -5.33 cm | Standard Error 0.71 |
| Group B (Placebo) | Change From Baseline in Waist Circumference at Week 24 | -4.18 cm | Standard Error 0.73 |
p-value: 0.1985Mixed Model Repeated Measures
Secondary
Number of Participants With Hypoglycemic Events During the Study
Number of participants experiencing one or more events of hypoglycemia at any point in the study
Time frame: Baseline to 24 weeks
Population: Intent to Treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Exenatide) | Number of Participants With Hypoglycemic Events During the Study | 33 participants |
| Group B (Placebo) | Number of Participants With Hypoglycemic Events During the Study | 30 participants |
p-value: 0.728Cochran-Mantel-Haenszel
Secondary
Rate of Hypoglycemic Events
Overall rate of hypoglycemia, adjusted for 1 year (ie., events of hypoglycemia per participant per year).
Time frame: 24 weeks
Population: Intent to Treat population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Rate of Hypoglycemic Events | 7.14 events per patient per year | Standard Error 1.45 |
| Group B (Placebo) | Rate of Hypoglycemic Events | 4.58 events per patient per year | Standard Error 1.43 |
p-value: 0.127ANOVA
Secondary
Ratio of Homeostatic Model Assessment-Beta Cell (HOMA-B) at Week 24 to HOMA-B at Baseline
Ratio of HOMA-B at Week 24 to HOMA-B at baseline (Week 0). HOMA-B is a computer solved model used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency. HOMA-B allows a quantitative assessment of the contributions of deficient beta cell function to the fasting hyperglycemia. HOMA-B is measured as a percent of the normal population (normal beta cell function = 100%, which is used as a reference in the calculation). The higher the percent the better for the participant.
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Ratio of Homeostatic Model Assessment-Beta Cell (HOMA-B) at Week 24 to HOMA-B at Baseline | 1.46 Ratio | Standard Error 0.12 |
| Group B (Placebo) | Ratio of Homeostatic Model Assessment-Beta Cell (HOMA-B) at Week 24 to HOMA-B at Baseline | 1.29 Ratio | Standard Error 0.1 |
p-value: 0.1827ANCOVA
Secondary
Ratio of Homeostatic Model Assessment-Insulin Sensitivity (HOMA-S) at Week 24 to HOMA-S at Baseline
Ratio of HOMA-S at Week 24 to HOMA-S at baseline, week 0. HOMA-S is a computer solved model used to predict the homeostatic concentrations which arise from varying degrees of insulin sensitivity. HOMA-S allows a quantitative assessment of the contributions of insulin sensitivity to the fasting hyperglycemia. HOMA-S is measured as a percent of the normal population (normal insulin sensitivity = 100%, which is used as a reference in the calculation). The higher the percent the better for the participant.
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Ratio of Homeostatic Model Assessment-Insulin Sensitivity (HOMA-S) at Week 24 to HOMA-S at Baseline | 1.08 Ratio | Standard Error 0.07 |
| Group B (Placebo) | Ratio of Homeostatic Model Assessment-Insulin Sensitivity (HOMA-S) at Week 24 to HOMA-S at Baseline | 0.97 Ratio | Standard Error 0.06 |
p-value: 0.1584ANCOVA
Secondary
Ratio of Triglycerides at Week 24 to Triglycerides at Baseline
Ratio of triglyceride levels at Week 24 to triglyceride levels at baseline, Week 0 (ie., triglycerides at Week 24 divided by triglycerides at baseline, Week 0). Triglycerides measured in mmol/L.
Time frame: baseline, Week 24
Population: Intent to Treat population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group A (Exenatide) | Ratio of Triglycerides at Week 24 to Triglycerides at Baseline | 0.83 Ratio | Standard Error 0.04 |
| Group B (Placebo) | Ratio of Triglycerides at Week 24 to Triglycerides at Baseline | 0.92 Ratio | Standard Error 0.04 |
p-value: 0.0654ANCOVA