Diabetes Mellitus, Type 2
Conditions
Keywords
diabetes, exendin, Amylin, Lilly, insulin aspart
Brief summary
This is a Phase 3, multicenter, open-label, comparator-controlled trial comparing the effect of exenatide twice daily to twice daily biphasic insulin aspart on glycemic control, as measured by hemoglobin A1c (HbA1c).
Interventions
DRUGexenatide
subcutaneous injection, twice daily; 5 mcg for 4 weeks followed by 10 mcg for 48 weeks
DRUGbiphasic insulin aspart
subcutaneous injection, twice daily; 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 the following for at least 3 months prior to screening: 1. \>=1500 mg/day immediate-release metformin or extended-release metformin and at least an optimally effective dose for brand of 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 11.0%, inclusive. * Patients have a body mass index \>25kg/m2 and \<40 kg/m2. * Female patients are not breastfeeding, and female patients of childbearing potential test negative for pregnancy, do not intend to become pregnant during the study, and agree to continue using a reliable method of birth control
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 previously, in this or any other study, received exenatide or glucagon-like peptide-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 have less than 5 years of remission history from any malignancy (other than basal cell or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate 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 biphasic insulin aspart, exenatide, or excipients contained in these agents. * Patients have characteristics contraindicating metformin or sulfonylurea use, according to product-specific label. * Patients have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine \>=1.5 mg/dL for males and \>=1.2 mg/dL for females. * Patients have obvious clinical signs or symptoms of liver disease, acute or chronic hepatitis, or alanine aminotransferase/serum glutamic pyruvic transaminase greater than three times the upper limit of the reference range. * Patients have known hemoglobinopathy or chronic anemia. * Patients have active proliferative retinopathy or macular edema. * Patients are receiving treatment for gastrointestinal disease with a drug directly affecting gastrointestinal motility, including but not limited to metoclopramide, cisapride, and chronic macrolide antibiotics. * 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 been treated for longer than 2 weeks with any of the following excluded medications within 3 months prior to screening: insulin, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides. * 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 Glcosylated Hemoglobin (HbA1c) | baseline, week 52 | Change in HbA1c from baseline to week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Weight | baseline, week 52 | Change in body weight from baseline to week 52. |
| Change in Fasting Serum Glucose | baseline, week 52 | Change in fasting serum glucose from baseline to week 52 |
| Percentage of Patients Achieving HbA1c <=7% | 52 weeks | Percentage of patients in each arm who had HbA1c \>7% at baseline and had HbA1c \<=7% at week 52 (percentage = \[number of subjects with HbA1c \<=7% at week 52 divided by number of subjects with HbA1c \>7% at baseline\] \* 100%). |
| Percentage of Patients With Hypoglycemic Events | 52 weeks | Percentage of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study (incidence of hypoglycemia = number of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study divided by the total number of patients who particiapted in the 52 week Parent Study |
| Change in Rate of Hypoglycemic Events | baseline, week 52 | Change in rate of hypoglycemic events per 30 days per patient from baseline to week 52 |
| Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | baseline, week 52 | Change in 7-point (pre-breakfast, after breakfast, pre-lunch, after lunch, pre-dinner, after dinner, 0300 hours) SMBG profile from baseline to week 52 |
Countries
Croatia, Germany, Greece, Italy, Netherlands, Portugal, Romania, Russia, Slovenia, Spain, Taiwan, United Kingdom
Participant flow
Pre-assignment details
Four patients withdrew from the study prior to receiving study drug.
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Arm subcutaneous injection, twice daily; 5 mcg for 4 weeks followed by 10 mcg for 48 weeks | 253 |
| Biphasic Insulin Aspart Arm subcutaneous injection, twice daily; titration to target blood glucose level | 248 |
| Total | 501 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 20 | 0 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Loss of Glucose Control | 2 | 2 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Patient Decision | 13 | 6 |
| Overall Study | Physician Decision | 5 | 3 |
| Overall Study | Protocol Violation | 14 | 12 |
Baseline characteristics
| Characteristic | Exenatide Arm | Biphasic Insulin Aspart Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 69 Participants | 74 Participants | 143 Participants |
| Age, Categorical Between 18 and 65 years | 184 Participants | 174 Participants | 358 Participants |
| Age, Continuous | 58.8 years STANDARD_DEVIATION 8.7 | 58.5 years STANDARD_DEVIATION 9.2 | 58.7 years STANDARD_DEVIATION 9 |
| Sex: Female, Male Female | 135 Participants | 122 Participants | 257 Participants |
| Sex: Female, Male Male | 118 Participants | 126 Participants | 244 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 179 / — | 128 / — |
| serious Total, serious adverse events | 19 / — | 11 / — |
Outcome results
Primary
Change in Glcosylated Hemoglobin (HbA1c)
Change in HbA1c from baseline to week 52
Time frame: baseline, week 52
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 Glcosylated Hemoglobin (HbA1c) | Baseline HbA1c | 8.59 percentage | Standard Error 0.07 |
| Exenatide Arm | Change in Glcosylated Hemoglobin (HbA1c) | Change in HbA1c at week 52 | -0.98 percentage | Standard Error 0.07 |
| Biphasic Insulin Aspart Arm | Change in Glcosylated Hemoglobin (HbA1c) | Baseline HbA1c | 8.65 percentage | Standard Error 0.07 |
| Biphasic Insulin Aspart Arm | Change in Glcosylated Hemoglobin (HbA1c) | Change in HbA1c at week 52 | -0.88 percentage | Standard Error 0.07 |
p-value: 0.253495% CI: [-0.28, 0.08]ANCOVA
Secondary
Change in 7-point Self-monitored Blood Glucose (SMBG) Profile
Change in 7-point (pre-breakfast, after breakfast, pre-lunch, after lunch, pre-dinner, after dinner, 0300 hours) SMBG profile from baseline to week 52
Time frame: baseline, week 52
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After breakfast: Change in SMBG at week 52 | -3.83 mmol/L | Standard Deviation 3.3 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After lunch: Change in SMBG at week 52 | -1.72 mmol/L | Standard Deviation 3.48 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Baseline SMBG | 9.57 mmol/L | Standard Deviation 2.34 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Baseline SMBG | 9.35 mmol/L | Standard Deviation 2.86 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Baseline SMBG | 9.38 mmol/L | Standard Deviation 2.86 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After breakfast: Baseline SMBG | 12.30 mmol/L | Standard Deviation 3.02 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After dinner: Baseline SMBG | 11.25 mmol/L | Standard Deviation 3.04 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Change in SMBG at week 52 | -1.47 mmol/L | Standard Deviation 3.01 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After dinner: Change in SMBG at week 52 | -3.11 mmol/L | Standard Deviation 3.76 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Change in SMBG at week 52 | -1.15 mmol/L | Standard Deviation 2.6 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Baseline SMBG | 9.08 mmol/L | Standard Deviation 2.63 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After lunch: Baseline SMBG | 11.18 mmol/L | Standard Deviation 3.14 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Change in SMBG at week 52 | -0.96 mmol/L | Standard Deviation 3.14 |
| Exenatide Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Change in SMBG at week 52 | -1.06 mmol/L | Standard Deviation 3.25 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Change in SMBG at week 52 | -1.95 mmol/L | Standard Deviation 3.13 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Baseline SMBG | 9.86 mmol/L | Standard Deviation 2.65 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-breakfast: Change in SMBG at week 52 | -1.68 mmol/L | Standard Deviation 2.33 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After breakfast: Baseline SMBG | 12.71 mmol/L | Standard Deviation 3.03 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After breakfast: Change in SMBG at week 52 | -3.06 mmol/L | Standard Deviation 3.26 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Baseline SMBG | 9.86 mmol/L | Standard Deviation 3.3 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-lunch: Change in SMBG at week 52 | -2.40 mmol/L | Standard Deviation 3.44 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After lunch: Baseline SMBG | 11.39 mmol/L | Standard Deviation 3.58 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After lunch: Change in SMBG at week 52 | -1.76 mmol/L | Standard Deviation 3.74 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Baseline SMBG | 9.57 mmol/L | Standard Deviation 3.03 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | Pre-dinner: Change in SMBG at week 52 | -1.52 mmol/L | Standard Deviation 3.42 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After dinner: Baseline SMBG | 11.68 mmol/L | Standard Deviation 3.27 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | After dinner: Change in SMBG at week 52 | -2.44 mmol/L | Standard Deviation 3.69 |
| Biphasic Insulin Aspart Arm | Change in 7-point Self-monitored Blood Glucose (SMBG) Profile | 3:00 AM: Baseline SMBG | 9.58 mmol/L | Standard Deviation 3.14 |
Secondary
Change in Body Weight
Change in body weight from baseline to week 52.
Time frame: baseline, week 52
Population: Intent to Treat, computed from the patients having both baseline and week 52 data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Body Weight | Baseline body weight | 85.51 kg | Standard Error 0.99 |
| Exenatide Arm | Change in Body Weight | Change in body weight at week 52 | -2.54 kg | Standard Error 0.17 |
| Biphasic Insulin Aspart Arm | Change in Body Weight | Baseline body weight | 83.38 kg | Standard Error 0.99 |
| Biphasic Insulin Aspart Arm | Change in Body Weight | Change in body weight at week 52 | 2.92 kg | Standard Error 0.17 |
p-value: 0.0001ANCOVA
Secondary
Change in Fasting Serum Glucose
Change in fasting serum glucose from baseline to week 52
Time frame: baseline, week 52
Population: Intent to Treat, computed from the patients having both baseline and week 52 data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Fasting Serum Glucose | Baseline fasting serum glucose | 11.00 mmol/L | Standard Error 0.18 |
| Exenatide Arm | Change in Fasting Serum Glucose | Change in fasting serum glucose at week 52 | -1.75 mmol/L | Standard Error 0.19 |
| Biphasic Insulin Aspart Arm | Change in Fasting Serum Glucose | Baseline fasting serum glucose | 11.30 mmol/L | Standard Error 0.18 |
| Biphasic Insulin Aspart Arm | Change in Fasting Serum Glucose | Change in fasting serum glucose at week 52 | -1.64 mmol/L | Standard Error 0.19 |
p-value: 0.6456ANCOVA
Secondary
Change in Rate of Hypoglycemic Events
Change in rate of hypoglycemic events per 30 days per patient from baseline to week 52
Time frame: baseline, week 52
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Arm | Change in Rate of Hypoglycemic Events | Baseline event rate | 0.22 events per 30 days per patient | Standard Error 0.07 |
| Exenatide Arm | Change in Rate of Hypoglycemic Events | Change in event rate at week 52 | 0.19 events per 30 days per patient | Standard Error 0.06 |
| Biphasic Insulin Aspart Arm | Change in Rate of Hypoglycemic Events | Baseline event rate | 0.18 events per 30 days per patient | Standard Error 0.07 |
| Biphasic Insulin Aspart Arm | Change in Rate of Hypoglycemic Events | Change in event rate at week 52 | 0.26 events per 30 days per patient | Standard Error 0.06 |
p-value: 0.3722ANCOVA
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 52 (percentage = \[number of subjects with HbA1c \<=7% at week 52 divided by number of subjects with HbA1c \>7% at baseline\] \* 100%).
Time frame: 52 weeks
Population: Last Observation Carried Forward; Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Arm | Percentage of Patients Achieving HbA1c <=7% | 31.7 percentage of participants |
| Biphasic Insulin Aspart Arm | Percentage of Patients Achieving HbA1c <=7% | 24.1 percentage of participants |
p-value: 0.0779Fisher Exact
Secondary
Percentage of Patients With Hypoglycemic Events
Percentage of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study (incidence of hypoglycemia = number of patients who experienced at least one episode of hypoglycemia at any point during the 52 week Parent Study divided by the total number of patients who particiapted in the 52 week Parent Study
Time frame: 52 weeks
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Arm | Percentage of Patients With Hypoglycemic Events | 53.0 percentage of participants |
| Biphasic Insulin Aspart Arm | Percentage of Patients With Hypoglycemic Events | 51.6 percentage of participants |
p-value: 0.7888Fisher Exact