Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, exendin-4, Amylin, Lilly
Brief summary
This Phase 3, open-label, multicenter study is designed to compare the effects of exenatide and insulin glargine (Lantus® injection) on beta-cell function in patients with type 2 diabetes mellitus using metformin.
Interventions
DRUGexenatide
subcutaneous injection, titrated up to a maximum of 20mcg three times a day in order to meet defined blood glucose targets
DRUGInsulin glargine
subcutaneous injection, once a day, titrated as necessary in order to meet defined blood glucose targets
DRUGMetformin
Patients usual dosage
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes, but otherwise healthy * HbA1c between 6.6% and 9.5%, inclusive. * Body mass index (BMI) of 25 kg/m2 to 40 kg/m2, inclusive. * Treated with a stable dose of metformin for at least 2 months prior to screening.
Exclusion criteria
* Patients previously in a study using exenatide. * Treated with oral anti-diabetic medications other than metformin within 2 months of screening (thiazolidinediones within 5 months of screening). * Treated with insulin within 3 months of screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Beta-cell Function After 52 Weeks of Therapy | Baseline (week -2) and 52 weeks | Treatment effect on beta-cell function as measured by the ratio of Week 52 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period \[i.e., clamp time 290 min to 300 min\]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 52 divided by arginine-stimulated insulin secretion at baseline \[week -2\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Beta-cell Function 4 Weeks After Cessation of Therapy | Baseline (week -2) and 56 weeks | Treatment effect on beta-cell function as measured by the ratio of Week 56 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period \[i.e., clamp time 290 min to 300 min\]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 56 divided by arginine-stimulated insulin secretion at baseline \[week -2\]). |
| Change in First Phase C-peptide Release | baseline (week -2), 52 weeks, and 56 weeks | Ratio of first phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to first phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline \[week -2\]). C-peptide is measured as a surrogate marker of insulin secretion. First phase C-peptide/insulin release is measured during the first ten minutes of glucose infusion during a hyperglycemic clamp procedure. |
| Change in Second Phase C-peptide Release | baseline (-2 weeks), 52 weeks, and 56 weeks | Ratio of second phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to second phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline \[week -2\]). C-peptide is measured as a surrogate marker of insulin secretion. Second phase C-peptide/insulin release is measured from time=10 minutes to time=80 minutes of glucose infusion during a hyperglycemic clamp procedure. |
| Change in Glycosylated Hemoglobin (HbA1c) | Week 0 and week 52 | Change in HbA1c from week 0 to week 52 (i.e., HbA1c at week 52 minus HbA1c at week 0). |
| Change in Fasting Plasma Glucose | 0 weeks and 52 weeks | Change in fasting plasma glucose from week 0 to week 52 (i.e., fasting plasma glucose at week 52 minus fasting plasma glucose at week 0). |
| Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 0 weeks and 52 weeks | SMBG measured at 7 time points (before and after breakfast, before and after lunch, before and after dinner, at bedtime). |
| Change in Body Weight | 0 weeks and 52 weeks | Change in body weight from week 0 to week 52 (i.e., body weight at week 52 minus body weight at week 0). |
| M-value at Baseline, Week 52 and Week 56 | baseline (week -2), 52 weeks, and 56 weeks | M-value at baseline (week -2), week 52 (end of on-drug period), and week 56 (during off-drug period). Insulin sensitivity was assessed during the euglycemic/hyperglycemic clamp test at baseline (week -2), week 52, and week 56. Insulin-mediated glucose uptake (M-value) was calculated as the mean glucose requirement during the 90-120 minute interval of the clamp. |
Countries
Finland, Netherlands, Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Arm 5 mcg twice a day for 4 weeks, followed by 10 mcg twice a day for 8 weeks. After 12 weeks, exenatide is titrated (up to a maximum of 20 mcg three times a day) based on periodic glycosylated hemoglobin (HbA1c) measurements and tolerability. | 36 |
| Insulin Glargine Arm Dosing starts at 10 IU/day, and is then titrated, based on daily fasting blood glucose measurements. | 33 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Off-drug Period (Week 52 to Week 64) | Loss of glucose control | 3 | 2 |
| Off-drug Period (Week 52 to Week 64) | Physician Decision | 0 | 1 |
| Off-drug Period (Week 52 to Week 64) | Withdrawal of consent | 2 | 1 |
| On-drug Period (Week 0 to Week 52) | Adverse Event | 5 | 0 |
| On-drug Period (Week 0 to Week 52) | Lost to Follow-up | 0 | 1 |
| On-drug Period (Week 0 to Week 52) | Physician Decision | 0 | 1 |
| On-drug Period (Week 0 to Week 52) | Withdrawal of consent | 1 | 1 |
Baseline characteristics
| Characteristic | Exenatide Arm | Insulin Glargine Arm | Total |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 8.4 | 58.3 years STANDARD_DEVIATION 7.3 | 58.4 years STANDARD_DEVIATION 7.8 |
| Body Mass Index (BMI) | 30.87 kg/m^2 STANDARD_DEVIATION 4.15 | 30.13 kg/m^2 STANDARD_DEVIATION 3.49 | 30.52 kg/m^2 STANDARD_DEVIATION 3.84 |
| Body weight | 90.56 kg STANDARD_DEVIATION 12.66 | 92.39 kg STANDARD_DEVIATION 13.56 | 91.44 kg STANDARD_DEVIATION 13.03 |
| Duration of diabetes | 5.72 years STANDARD_DEVIATION 4.7 | 3.97 years STANDARD_DEVIATION 3.62 | 4.88 years STANDARD_DEVIATION 4.28 |
| Glycosylated hemoglobin (HbA1c) | 7.58 percentage STANDARD_DEVIATION 0.89 | 7.41 percentage STANDARD_DEVIATION 0.81 | 7.50 percentage STANDARD_DEVIATION 0.85 |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 24 Participants |
| Sex: Female, Male Male | 23 Participants | 22 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 36 | 31 / 33 |
| serious Total, serious adverse events | 3 / 36 | 1 / 33 |
Outcome results
Primary
Beta-cell Function After 52 Weeks of Therapy
Treatment effect on beta-cell function as measured by the ratio of Week 52 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period \[i.e., clamp time 290 min to 300 min\]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 52 divided by arginine-stimulated insulin secretion at baseline \[week -2\]).
Time frame: Baseline (week -2) and 52 weeks
Population: Evaluable population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Arm | Beta-cell Function After 52 Weeks of Therapy | 2.89 ratio | Standard Error 0.27 |
| Insulin Glargine Arm | Beta-cell Function After 52 Weeks of Therapy | 1.15 ratio | Standard Error 0.11 |
p-value: 0.0001ANCOVA
Secondary
Beta-cell Function 4 Weeks After Cessation of Therapy
Treatment effect on beta-cell function as measured by the ratio of Week 56 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period \[i.e., clamp time 290 min to 300 min\]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 56 divided by arginine-stimulated insulin secretion at baseline \[week -2\]).
Time frame: Baseline (week -2) and 56 weeks
Population: Evaluable population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Arm | Beta-cell Function 4 Weeks After Cessation of Therapy | 1.02 ratio | Standard Error 0.06 |
| Insulin Glargine Arm | Beta-cell Function 4 Weeks After Cessation of Therapy | 1.08 ratio | Standard Error 0.07 |
p-value: 0.4185ANCOVA
Secondary
Change in Body Weight
Change in body weight from week 0 to week 52 (i.e., body weight at week 52 minus body weight at week 0).
Time frame: 0 weeks and 52 weeks
Population: Intent to treat population. Last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Arm | Change in Body Weight | -3.80 kg | Standard Error 0.87 |
| Insulin Glargine Arm | Change in Body Weight | 0.75 kg | Standard Error 0.95 |
p-value: <0.0001ANCOVA
Secondary
Change in Fasting Plasma Glucose
Change in fasting plasma glucose from week 0 to week 52 (i.e., fasting plasma glucose at week 52 minus fasting plasma glucose at week 0).
Time frame: 0 weeks and 52 weeks
Population: Intent to treat population. Last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Arm | Change in Fasting Plasma Glucose | -1.53 mmol/L | Standard Error 0.25 |
| Insulin Glargine Arm | Change in Fasting Plasma Glucose | -3.10 mmol/L | Standard Error 0.27 |
p-value: <0.0001ANCOVA
Secondary
Change in First Phase C-peptide Release
Ratio of first phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to first phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline \[week -2\]). C-peptide is measured as a surrogate marker of insulin secretion. First phase C-peptide/insulin release is measured during the first ten minutes of glucose infusion during a hyperglycemic clamp procedure.
Time frame: baseline (week -2), 52 weeks, and 56 weeks
Population: Evaluable population. Last observation carried forward.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in First Phase C-peptide Release | 52 weeks | 1.72 ratio | Standard Error 0.11 |
| Exenatide Arm | Change in First Phase C-peptide Release | 56 weeks | 0.95 ratio | Standard Error 0.05 |
| Insulin Glargine Arm | Change in First Phase C-peptide Release | 52 weeks | 1.13 ratio | Standard Error 0.07 |
| Insulin Glargine Arm | Change in First Phase C-peptide Release | 56 weeks | 1.06 ratio | Standard Error 0.06 |
Comparison: Statistical analysis at week 52.p-value: <0.0001ANCOVA
Comparison: Statistical analysis at week 56.p-value: 0.1188ANCOVA
Secondary
Change in Glycosylated Hemoglobin (HbA1c)
Change in HbA1c from week 0 to week 52 (i.e., HbA1c at week 52 minus HbA1c at week 0).
Time frame: Week 0 and week 52
Population: Intent to treat population. Last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Arm | Change in Glycosylated Hemoglobin (HbA1c) | -0.97 percent | Standard Error 0.14 |
| Insulin Glargine Arm | Change in Glycosylated Hemoglobin (HbA1c) | -0.87 percent | Standard Error 0.15 |
p-value: 0.5522ANCOVA
Secondary
Change in Second Phase C-peptide Release
Ratio of second phase C-peptide response to glucose at 52 weeks (end of on-drug period) and 56 weeks (during off-drug period) compared to second phase C-peptide response to glucose at baseline (i.e., C-peptide response to glucose at week 52 or week 56 divided by C-peptide response to glucose at baseline \[week -2\]). C-peptide is measured as a surrogate marker of insulin secretion. Second phase C-peptide/insulin release is measured from time=10 minutes to time=80 minutes of glucose infusion during a hyperglycemic clamp procedure.
Time frame: baseline (-2 weeks), 52 weeks, and 56 weeks
Population: Evaluable population. Last observation carried forward.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Second Phase C-peptide Release | 52 weeks | 2.88 ratio | Standard Error 0.18 |
| Exenatide Arm | Change in Second Phase C-peptide Release | 56 weeks | 1.00 ratio | Standard Error 0.05 |
| Insulin Glargine Arm | Change in Second Phase C-peptide Release | 52 weeks | 1.01 ratio | Standard Error 0.07 |
| Insulin Glargine Arm | Change in Second Phase C-peptide Release | 56 weeks | 1.08 ratio | Standard Error 0.06 |
Comparison: Statistical analysis at week 52.p-value: <0.0001ANCOVA
Comparison: Statistical analysis at week 56.p-value: 0.1996ANCOVA
Secondary
M-value at Baseline, Week 52 and Week 56
M-value at baseline (week -2), week 52 (end of on-drug period), and week 56 (during off-drug period). Insulin sensitivity was assessed during the euglycemic/hyperglycemic clamp test at baseline (week -2), week 52, and week 56. Insulin-mediated glucose uptake (M-value) was calculated as the mean glucose requirement during the 90-120 minute interval of the clamp.
Time frame: baseline (week -2), 52 weeks, and 56 weeks
Population: Evaluable population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | M-value at Baseline, Week 52 and Week 56 | baseline (week -2) | 2.24 mg/min/kg | Standard Error 0.39 |
| Exenatide Arm | M-value at Baseline, Week 52 and Week 56 | week 52 | 3.18 mg/min/kg | Standard Error 0.42 |
| Exenatide Arm | M-value at Baseline, Week 52 and Week 56 | week 56 | 3.19 mg/min/kg | Standard Error 0.44 |
| Insulin Glargine Arm | M-value at Baseline, Week 52 and Week 56 | baseline (week -2) | 2.79 mg/min/kg | Standard Error 0.26 |
| Insulin Glargine Arm | M-value at Baseline, Week 52 and Week 56 | week 52 | 3.85 mg/min/kg | Standard Error 0.32 |
| Insulin Glargine Arm | M-value at Baseline, Week 52 and Week 56 | week 56 | 2.81 mg/min/kg | Standard Error 0.29 |
Secondary
Seven Point Self Monitored Blood Glucose (SMBG) Measurements
SMBG measured at 7 time points (before and after breakfast, before and after lunch, before and after dinner, at bedtime).
Time frame: 0 weeks and 52 weeks
Population: Intent to treat population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-breakfast measurement (week 0) | 8.92 mmol/L | Standard Deviation 1.8 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-breakfast measurement (week 52) | 7.27 mmol/L | Standard Deviation 1.63 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-breakfast measurement (week 0) | 11.00 mmol/L | Standard Deviation 2.58 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-breakfast measurement (week 52) | 6.98 mmol/L | Standard Deviation 2.42 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-lunch measurement (week 0) | 8.14 mmol/L | Standard Deviation 2.25 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-lunch measurement (week 52) | 6.52 mmol/L | Standard Deviation 1.52 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-lunch measurement (week 0) | 9.90 mmol/L | Standard Deviation 2.54 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-lunch measurement (week 52) | 7.97 mmol/L | Standard Deviation 2.01 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-dinner measurement (week 0) | 8.38 mmol/L | Standard Deviation 2.4 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-dinner measurement (week 52) | 7.53 mmol/L | Standard Deviation 2.63 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-dinner measurement (week 0) | 10.42 mmol/L | Standard Deviation 2.42 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-dinner measurement (week 52) | 6.98 mmol/L | Standard Deviation 2.25 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Bedtime measurement (week 0) | 9.76 mmol/L | Standard Deviation 2.44 |
| Exenatide Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Bedtime measurement (week 52) | 7.61 mmol/L | Standard Deviation 2.11 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-dinner measurement (week 0) | 10.26 mmol/L | Standard Deviation 2.82 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-breakfast measurement (week 0) | 8.38 mmol/L | Standard Deviation 1.91 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-lunch measurement (week 52) | 8.15 mmol/L | Standard Deviation 1.77 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-breakfast measurement (week 52) | 5.63 mmol/L | Standard Deviation 0.85 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Bedtime measurement (week 0) | 9.85 mmol/L | Standard Deviation 3.09 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-breakfast measurement (week 0) | 11.17 mmol/L | Standard Deviation 3.3 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-dinner measurement (week 0) | 8.07 mmol/L | Standard Deviation 2.48 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-breakfast measurement (week 52) | 7.53 mmol/L | Standard Deviation 2.16 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-dinner measurement (week 52) | 8.81 mmol/L | Standard Deviation 2.03 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-lunch measurement (week 0) | 8.54 mmol/L | Standard Deviation 2.51 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-dinner measurement (week 52) | 6.98 mmol/L | Standard Deviation 2.04 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Pre-lunch measurement (week 52) | 6.24 mmol/L | Standard Deviation 1.66 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | Bedtime measurement (week 52) | 8.03 mmol/L | Standard Deviation 2.82 |
| Insulin Glargine Arm | Seven Point Self Monitored Blood Glucose (SMBG) Measurements | 2-hour post-lunch measurement (week 0) | 10.52 mmol/L | Standard Deviation 2.96 |