Diabetes Mellitus, Type 2
Conditions
Keywords
Diabetes, Insulin glargine, comparator, Amylin, Lilly
Brief summary
This is a multicenter, comparator-controlled, open-label, randomized, two-arm, parallel trial to compare the effect of exenatide twice daily and insulin glargine on glycemic control, as measured by hemoglobin A1c (HbA1c).
Interventions
DRUGExenatide (AC2993)
subcutaneous injection, twice daily; 5 mcg for 4 weeks followed by 10 mcg for 22 weeks
DRUGInsulin glargine
subcutaneous injection, once daily; forced titration to target blood glucose level
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
* Patients have been treated with a stable dose of one of the following for at least 3 months prior to screening: 1. 1500 to 2550 mg/day immediate-release metformin (or 1500 to 2000 mg/day extended-release metformin) and at least an optimally effective dose of a sulfonylurea, or 2. a fixed-dose sulfonylurea/metformin combination therapy with the same sulfonylurea and metformin requirements as for the individual components. * HbA1c between 7.0% and 10.0%, inclusive. * History of stable body weight (not varying by \>10% for at least three months prior to screening). * Female patients are not breastfeeding, and female patients of childbearing potential (not surgically sterilized and between menarche and 1-year postmenopause)
Exclusion criteria
* Patients are investigator site personnel directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study. * Patients are employed by Lilly or Amylin. * Patients have participated in this study previously or any other study using AC2993 or GLP-1 analogs. * Patients have participated in an interventional medical, surgical, or pharmaceutical study within 30 days prior to screening. This criterion includes drugs that have not received regulatory approval for any indication at the time of study entry. * Patients have had greater than three episodes of severe hypoglycemia within 6 months prior to screening. * Patients are undergoing therapy for a malignancy, other than basal cell or squamous cell skin cancer. * Patients have cardiac disease that is Class III or IV, according to the New York Heart Association criteria. * Patients have a known allergy or hypersensitivity to insulin glargine, AC2993, or excipients contained in these agents. * Patients have characteristics contraindicating metformin or sulfonylurea use, according to product-specific label, in the opinion of the investigator. * Patients have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine \>=1.5 mg/dL for males and \>=1.3 mg/dL for females. * Patients have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase/serum glutamicpyruvic transaminase greater than three times the upper limit of the reference range. * Patients have known hemoglobinopathy or chronic anemia. * Patients are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within 2 weeks immediately prior to screening. * Patients have used any prescription drug to promote weight loss within 3 months prior to screening. * Patients have any other condition (including known drug or alcohol abuse or psychiatric disorder) that precludes them from following and completing the protocol, in the opinion of the investigator. * Patients fail to satisfy the investigator of suitability to participate for any other reason.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Glycosylated Hemoglobin (HbA1c) | Baseline, week 26 | Change in HbA1c from baseline to week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | Baseline, week 26 | Change in body weight from baseline to week 26 |
| Change in Fasting Serum Glucose | Baseline, week 26 | Change in fasting serum glucose from baseline to week 26 |
| Percentage of Patients Achieving HbA1c <=7% | 26 weeks | Percentage of patients in each arm who had HbA1c \>7% at baseline and had HbA1c \<=7% at week 26 (percentage = \[number of subjects with HbA1c \<=7% at week 26 divided by number of subjects with HbA1c \>7% at baseline\] \* 100%). |
| Percentage of Patients With Hypoglycemic Events | 26 weeks | Percentage of patients who experienced at least one episode of hypoglycemia at any point during the 26 week Parent Study (incidence of hypoglycemia = number of patients who experienced at least one episode of hypoglycemia at any point during the 26 week Parent Study divided by the total number of patients who participated in the 26 week Parent Study |
| Change in Rate of Hypoglycemic Events | Baseline, week 26 | Change in rate of hypoglycemic events per 30 days per patient from baseline to week 26 |
| Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Baseline, week 26 | Change in 7-point (pre-breakfast, 2 hour post breakfast, pre-lunch, 2 hour post lunch, pre-dinner, 2 hour post dinner, 0300 hours) SMBG profile from baseline to week 26 |
Countries
Australia, Belgium, Brazil, Finland, Germany, Netherlands, Norway, Poland, Portugal, Puerto Rico, Spain, Sweden, United States
Participant flow
Pre-assignment details
Two patients were lost to follow-up after receiving study drug, and it is not known if they took at least one dose of the drug. For purposes of data analysis, these patients were classified as untreated.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Arm Exenatide subcutaneous injection twice daily for 26 weeks (5mcg for 4 weeks followed by 10mcg for 22 weeks) | 282 |
| Insulin Glargine Arm Insulin glargine subcutaneous injection once daily for 26 weeks (forced titration to target blood glucose level) | 267 |
| Total | 549 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 27 | 2 |
| Overall Study | Loss of Glucose Control | 4 | 0 |
| Overall Study | Lost to Follow-up | 5 | 7 |
| Overall Study | Patient Decision | 8 | 4 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 10 | 11 |
Baseline characteristics
| Characteristic | Exenatide Arm | Insulin Glargine Arm | Total |
|---|---|---|---|
| Age, Continuous | 59.80 years STANDARD_DEVIATION 8.82 | 57.96 years STANDARD_DEVIATION 9.46 | 58.91 years STANDARD_DEVIATION 9.13 |
| Sex: Female, Male Female | 127 Participants | 116 Participants | 243 Participants |
| Sex: Female, Male Male | 155 Participants | 151 Participants | 306 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 226 / — | 160 / — |
| serious Total, serious adverse events | 8 / — | 10 / — |
Outcome results
Primary
Change in Glycosylated Hemoglobin (HbA1c)
Change in HbA1c from baseline to week 26
Time frame: Baseline, week 26
Population: Last Observation Carried Forward; Intent to Treat, computed from the patients having both baseline and post baseline data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Glycosylated Hemoglobin (HbA1c) | Baseline HbA1c | 8.13 percentage | Standard Error 0.07 |
| Exenatide Arm | Change in Glycosylated Hemoglobin (HbA1c) | Change in HbA1c at week 26 | -1.00 percentage | Standard Error 0.06 |
| Insulin Glargine Arm | Change in Glycosylated Hemoglobin (HbA1c) | Baseline HbA1c | 8.19 percentage | Standard Error 0.07 |
| Insulin Glargine Arm | Change in Glycosylated Hemoglobin (HbA1c) | Change in HbA1c at week 26 | -1.05 percentage | Standard Error 0.06 |
p-value: 0.460295% CI: [-0.09, 0.2]ANCOVA
Secondary
Change in 7-point Self-monitored Blood Glucose (SMBG) Profile
Change in 7-point (pre-breakfast, 2 hour post breakfast, pre-lunch, 2 hour post lunch, pre-dinner, 2 hour post dinner, 0300 hours) SMBG profile from baseline to week 26
Time frame: Baseline, week 26
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Baseline SMBG | 9.47 mmol/L | Standard Error 0.169 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Change in SMBG at week 26 | -1.25 mmol/L | Standard Error 0.13 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post breatfast: Baseline SMBG | 12.51 mmol/L | Standard Error 0.22 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post breakfast: Change in SMBG at week 26 | -3.77 mmol/L | Standard Error 0.171 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Baseline SMBG | 9.61 mmol/L | Standard Error 0.218 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Change in SMBG at week 26 | -1.50 mmol/L | Standard Error 0.156 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post lunch: Baseline SMBG | 11.15 mmol/L | Standard Error 0.222 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post lunch: Change in SMBG at week 26 | -1.68 mmol/L | Standard Error 0.173 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Baseline SMBG | 9.46 mmol/L | Standard Error 0.211 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Change in SMBG at week 26 | -1.15 mmol/L | Standard Error 0.156 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post dinner: Baseline SMBG | 11.17 mmol/L | Standard Error 0.206 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post dinner: Change in SMBG at week 26 | -3.06 mmol/L | Standard Error 0.172 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Baseline SMBG | 9.02 mmol/L | Standard Error 0.189 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Change in SMBG at week 26 | -1.05 mmol/L | Standard Error 0.169 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post dinner: Baseline SMBG | 11.49 mmol/L | Standard Error 0.211 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Baseline SMBG | 9.50 mmol/L | Standard Error 0.173 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post lunch: Change in SMBG at week 26 | -1.69 mmol/L | Standard Error 0.176 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Change in SMBG at week 26 | -2.56 mmol/L | Standard Error 0.132 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Baseline SMBG | 9.36 mmol/L | Standard Error 0.192 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post breatfast: Baseline SMBG | 12.36 mmol/L | Standard Error 0.226 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Baseline SMBG | 9.35 mmol/L | Standard Error 0.216 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post breakfast: Change in SMBG at week 26 | -2.86 mmol/L | Standard Error 0.174 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post dinner: Change in SMBG at week 26 | -1.65 mmol/L | Standard Error 0.175 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Baseline SMBG | 9.47 mmol/L | Standard Error 0.224 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Change in SMBG at week 26 | -1.72 mmol/L | Standard Error 0.159 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Change in SMBG at week 26 | -1.93 mmol/L | Standard Error 0.158 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Change in SMBG at week 26 | -1.97 mmol/L | Standard Error 0.169 |
| Insulin Glargine Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 2hr post lunch: Baseline SMBG | 10.96 mmol/L | Standard Error 0.226 |
Secondary
Change in Body Weight
Change in body weight from baseline to week 26
Time frame: Baseline, week 26
Population: Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Body Weight | Baseline body weight | 88.42 kg | Standard Error 1.16 |
| Exenatide Arm | Change in Body Weight | Change in body weight at week 26 | -2.32 kg | Standard Error 0.21 |
| Insulin Glargine Arm | Change in Body Weight | Baseline body weight | 89.25 kg | Standard Error 1.2 |
| Insulin Glargine Arm | Change in Body Weight | Change in body weight at week 26 | 1.75 kg | Standard Error 0.21 |
p-value: <0.0001ANCOVA
Secondary
Change in Fasting Serum Glucose
Change in fasting serum glucose from baseline to week 26
Time frame: Baseline, week 26
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Fasting Serum Glucose | Baseline fasting serum glucose | 10.27 mmol/L | Standard Error 0.21 |
| Exenatide Arm | Change in Fasting Serum Glucose | Change in fasting serum glucose at week 26 | -1.22 mmol/L | Standard Error 0.19 |
| Insulin Glargine Arm | Change in Fasting Serum Glucose | Baseline fasting serum glucose | 10.46 mmol/L | Standard Error 0.21 |
| Insulin Glargine Arm | Change in Fasting Serum Glucose | Change in fasting serum glucose at week 26 | -2.86 mmol/L | Standard Error 0.19 |
p-value: <0.0001ANCOVA
Secondary
Change in Rate of Hypoglycemic Events
Change in rate of hypoglycemic events per 30 days per patient from baseline to week 26
Time frame: Baseline, week 26
Population: Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Rate of Hypoglycemic Events | Change in event rate at week 26 | 0.23 events per 30 days per patient | Standard Error 0.06 |
| Exenatide Arm | Change in Rate of Hypoglycemic Events | Baseline event rate | 0.09 events per 30 days per patient | Standard Error 0.04 |
| Insulin Glargine Arm | Change in Rate of Hypoglycemic Events | Baseline event rate | 0.11 events per 30 days per patient | Standard Error 0.04 |
| Insulin Glargine Arm | Change in Rate of Hypoglycemic Events | Change in event rate at week 26 | 0.29 events per 30 days per patient | Standard Error 0.06 |
p-value: 0.3385ANCOVA
Secondary
Percentage of Patients Achieving HbA1c <=7%
Percentage of patients in each arm who had HbA1c \>7% at baseline and had HbA1c \<=7% at week 26 (percentage = \[number of subjects with HbA1c \<=7% at week 26 divided by number of subjects with HbA1c \>7% at baseline\] \* 100%).
Time frame: 26 weeks
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Arm | Percentage of Patients Achieving HbA1c <=7% | 46.43 percentage of participants |
| Insulin Glargine Arm | Percentage of Patients Achieving HbA1c <=7% | 48.03 percentage of participants |
p-value: 0.7839Fisher Exact
Secondary
Percentage of Patients With Hypoglycemic Events
Percentage of patients who experienced at least one episode of hypoglycemia at any point during the 26 week Parent Study (incidence of hypoglycemia = number of patients who experienced at least one episode of hypoglycemia at any point during the 26 week Parent Study divided by the total number of patients who participated in the 26 week Parent Study
Time frame: 26 weeks
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Arm | Percentage of Patients With Hypoglycemic Events | 55.32 percentage of participants |
| Insulin Glargine Arm | Percentage of Patients With Hypoglycemic Events | 59.93 percentage of participants |
p-value: 0.3002Fisher Exact