Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, once weekly, Byetta, Amylin, Lilly
Brief summary
Previous studies have suggested that a once-weekly formulation of exenatide may provide sustained glycemic control. These previous studies of exenatide once weekly have been conducted in non-Asian populations, so this study has been developed to support the local regulatory requirements of China, Korea, Japan, India, and Taiwan.
Interventions
2.0mg subcutaneous injection, once a week
5mcg subcutaneous injection twice a day (4 weeks), 10mcg subcutaneous injection twice a day (22 weeks)
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have been diagnosed with type 2 diabetes. * Have suboptimal glycemic control as evidenced by an HbA1c between 7.1% and 11.0% inclusive. * Have a body mass index (BMI) of \>21 kg/m2 and \<35 kg/m2, inclusive. * Have a history of stable body weight (not varying by \>5% for at least 90 days prior to study start). * Have been treated with a stable dose regimen of Met, SU, TZD, Met plus SU, Met plus TZD, or SU plus TZD for at least 90 days prior to study start.
Exclusion criteria
* Have any contraindication for the OAD(s) that they use. * Have a known allergy or hypersensitivity to exenatide BID, exenatide QW, or excipients contained in these agents. * Have received chronic \>14 consecutive days) systemic glucocorticoid therapy by oral, intravenous (IV), or intramuscular (IM) route or intra-articular steroid injection within 4 weeks prior to study start or are regularly treated with potent, inhaled steroids that are known to have a high rate of systemic absorption. * Have been treated with drugs that promote weight loss (for example, GLP-1 analogue, orlistat, sibutramine, phenylpropanolamine, or similar over-the-counter medications) within 90 days of study start. * Have been treated for \>2 weeks with any of the following excluded medications within 90 days prior to study start: * Insulin * Dipeptidyl peptidase (DPP)-4 inhibitors (for example, sitagliptin or vildagliptin) * Pramlintide acetate * Drugs that directly affect gastrointestinal motility, including, but not limited to: Reglan® (metoclopramide), Propulsid® (cisapride), and chronic macrolide antibiotics. * Have had prior exposure to exenatide * Have previously completed or withdrawn from this study or any other study investigating exenatide BID or QW. * 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 Targets <=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 from baseline to Week 26. |
| Change in Body Weight (BW) From Baseline to Week 26 | Baseline, Week 26 | Change in BW from baseline to Week 26. |
| Change in Total Cholesterol (TC) From Baseline to Week 26 | Baseline, Week 26 | Change in TC from baseline to Week 26. |
| Percentage of Patients Achieving HbA1c Targets <=7% at Week 26 | Baseline, Week 26 | Percentage of patients achieving HbA1c \<=7% at Week 26 (for patients with HbA1c \>7% at baseline). |
| Ratio of Triglycerides (TG) at Week 26 to Baseline | Baseline, Week 26 | Ratio of TG (measured in mg/dL) at Week 26 to baseline. Log(Post-baseline TG) - log(Baseline TG); change from baseline to Week 26 is presented as ratio of Week 26 to baseline. |
| Change in Blood Pressure From Baseline to Week 26 | Baseline, Week 26 | Change in systolic blood pressure and diastolic blood pressure from baseline to Week 26. |
| Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | 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 sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. Event rate per subject year was calculated for each subject: (number of events observed from a subject/exposure from a subject)\*365.25 where exposure = last post-baseline visit date - baseline visit date. Mean and Standard Error were then derived from ITT. |
| Change in High-Density Lipoprotein (HDL) From Baseline to Week 26 | Baseline, Week 26 | Change in HDL from baseline to Week 26. |
Countries
China, India, Japan, South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly Subcutaneous injection of 2 mg exenatide, once a week | 340 |
| Exenatide Twice Daily Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 22 weeks) | 338 |
| Total | 678 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 15 | 36 |
| Overall Study | Entry Criteria Not Met | 1 | 0 |
| Overall Study | Lack of Efficacy-Loss of Glucose Control | 2 | 2 |
| Overall Study | Lost to follow up | 0 | 2 |
| Overall Study | Physician Decision | 2 | 4 |
| Overall Study | Protocol Violation | 9 | 18 |
| Overall Study | Sponsor Decision | 5 | 5 |
| Overall Study | Withdrawal by Subject | 5 | 12 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly | Exenatide Twice Daily | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 65 Participants | 64 Participants | 129 Participants |
| Age, Categorical Between 18 and 65 years | 275 Participants | 274 Participants | 549 Participants |
| Age, Continuous | 55.4 years STANDARD_DEVIATION 10.59 | 56.2 years STANDARD_DEVIATION 9.99 | 55.8 years STANDARD_DEVIATION 10.3 |
| Background Oral Antidiabetic Agent (OAD) Metformin (MET) | 62 participants | 60 participants | 122 participants |
| Background Oral Antidiabetic Agent (OAD) MET+Sulfonylurea (SU) | 210 participants | 216 participants | 426 participants |
| Background Oral Antidiabetic Agent (OAD) MET+SU+Thiazolidinedione (TZD) | 6 participants | 10 participants | 16 participants |
| Background Oral Antidiabetic Agent (OAD) MET+TZD | 12 participants | 9 participants | 21 participants |
| Background Oral Antidiabetic Agent (OAD) SU | 30 participants | 29 participants | 59 participants |
| Background Oral Antidiabetic Agent (OAD) SU+TZD | 18 participants | 12 participants | 30 participants |
| Background Oral Antidiabetic Agent (OAD) TZD | 2 participants | 2 participants | 4 participants |
| Glycosylated hemoglobin (HbA1c) | 8.7 percentage of total hemoglobin STANDARD_DEVIATION 1.04 | 8.7 percentage of total hemoglobin STANDARD_DEVIATION 1.03 | 8.7 percentage of total hemoglobin STANDARD_DEVIATION 1.03 |
| Sex: Female, Male Female | 157 Participants | 154 Participants | 311 Participants |
| Sex: Female, Male Male | 183 Participants | 184 Participants | 367 Participants |
| Weight | 69.6 kg STANDARD_DEVIATION 12.44 | 70.4 kg STANDARD_DEVIATION 12.09 | 70.0 kg STANDARD_DEVIATION 12.26 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 131 / 340 | 150 / 338 |
| serious Total, serious adverse events | 13 / 340 | 8 / 338 |
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: Randomized patients received 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. | -1.43 percentage of total hemoglobin | Standard Error 0.07 |
| Exenatide Twice Daily | Change in HbA1c From Baseline to Week 26. | -1.12 percentage of total hemoglobin | Standard Error 0.07 |
Comparison: MMRM analysis of covariance (ANCOVA) model includes treatment, baseline HbA1c, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects. Power: 306 patients per treatment group provides approximately 98% power to detect a true difference between treatments of 0.4% in change in HbA1c from baseline with a 2-sided t test at a significance level of 0.05, assuming a common standard deviation of 1.2%.p-value: <0.00195% CI: [-0.49, -0.14]Mixed Models Analysis
Secondary
Assessment of Event Rate of Treatment-emergent Hypoglycemic Events
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 sign or symptom associated with hypoglycemia that is either self-treated by the patient or resolves on its own AND has a concurrent finger stick blood glucose \<3.0 mmol/L (54 mg/dL) and not classified as major hypoglycemia. Event rate per subject year was calculated for each subject: (number of events observed from a subject/exposure from a subject)\*365.25 where exposure = last post-baseline visit date - baseline visit date. Mean and Standard Error were then derived from ITT.
Time frame: Baseline to Week 26
Population: ITT Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.24 events per subject-year | Standard Error 0.069 |
| Exenatide Twice Daily | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.59 events per subject-year | Standard Error 0.18 |
| Exenatide Twice Daily | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.01 events per subject-year | Standard Error 0.007 |
| Exenatide Once Weekly Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.03 events per subject-year | Standard Error 0.027 |
| Exenatide Twice Daily Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Major Hypoglycemia | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Twice Daily Without SU Use at Screening | Assessment of Event Rate of Treatment-emergent Hypoglycemic Events | Minor Hypoglycemia | 0.11 events per subject-year | Standard Error 0.113 |
Secondary
Change in Blood Pressure From Baseline to Week 26
Change in systolic blood pressure and diastolic blood pressure 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. Missing data at endpoint was not imputed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 26 | Systolic Blood Pressure | -5.33 mmHg | Standard Deviation 15.99 |
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 26 | Diastolic Blood Pressure | -1.47 mmHg | Standard Deviation 9.52 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 26 | Systolic Blood Pressure | -5.22 mmHg | Standard Deviation 16.23 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 26 | Diastolic Blood Pressure | -2.24 mmHg | Standard Deviation 9.56 |
Secondary
Change in Body Weight (BW) From Baseline to Week 26
Change in BW 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 | -1.63 kg | Standard Error 0.16 |
| Exenatide Twice Daily | Change in Body Weight (BW) From Baseline to Week 26 | -2.45 kg | Standard Error 0.16 |
Comparison: MMRM ANCOVA model includes treatment, baseline BW, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects.p-value: <0.00195% CI: [0.39, 1.25]Mixed Models Analysis
Secondary
Change in Fasting Serum Glucose (FSG) From Baseline to Week 26
Change in FSG 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 | -40.57 mg/dL | Standard Error 2.36 |
| Exenatide Twice Daily | Change in Fasting Serum Glucose (FSG) From Baseline to Week 26 | -23.90 mg/dL | Standard Error 2.45 |
Comparison: MMRM ANCOVA model includes treatment, baseline FSG, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects.p-value: <0.00195% CI: [-22.5, -10.83]Mixed Models Analysis
Secondary
Change in High-Density Lipoprotein (HDL) From Baseline to Week 26
Change in HDL 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 (HDL) From Baseline to Week 26 | -0.11 mg/dL | Standard Error 0.41 |
| Exenatide Twice Daily | Change in High-Density Lipoprotein (HDL) From Baseline to Week 26 | -0.48 mg/dL | Standard Error 0.43 |
Comparison: MMRM ANCOVA model includes treatment, baseline HDL, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects.p-value: 0.47695% CI: [-0.65, 1.38]Mixed Models Analysis
Secondary
Change in Total Cholesterol (TC) From Baseline to Week 26
Change in TC 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 (TC) From Baseline to Week 26 | -9.41 mg/dL | Standard Error 1.96 |
| Exenatide Twice Daily | Change in Total Cholesterol (TC) From Baseline to Week 26 | -8.10 mg/dL | Standard Error 2.04 |
Comparison: MMRM ANCOVA model includes treatment, baseline TC, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects.p-value: 0.60995% CI: [-6.33, 3.71]Mixed Models Analysis
Secondary
Percentage of Patients Achieving HbA1c Targets <=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 \> target 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. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c Targets <=6.5% at Week 26 | 26.0 percentage of patients |
| Exenatide Twice Daily | Percentage of Patients Achieving HbA1c Targets <=6.5% at Week 26 | 15.5 percentage of patients |
Comparison: Percentage of patients achieving HbA1c target \<=6.5% at Week 26 were compared between treatments using a CMH test, in which country and background OAD served as the stratification factors.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Patients Achieving HbA1c Targets <=7% at Week 26
Percentage of patients achieving HbA1c \<=7% at Week 26 (for patients with HbA1c \>7% at baseline).
Time frame: Baseline, Week 26
Population: ITT Population. Only patients with baseline HbA1c \> target 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. Missing data at endpoint was imputed using last observation carried forward (LOCF) approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Patients Achieving HbA1c Targets <=7% at Week 26 | 46.7 percentage of patients |
| Exenatide Twice Daily | Percentage of Patients Achieving HbA1c Targets <=7% at Week 26 | 35.7 percentage of patients |
Comparison: Percentage of patients achieving HbA1c target \<=7% at Week 26 were compared between treatments using a Cochran-Mantel-Haenszel (CMH) test, in which country and background OAD served as the stratification factors.p-value: 0.003Cochran-Mantel-Haenszel
Secondary
Ratio of Triglycerides (TG) at Week 26 to Baseline
Ratio of TG (measured in mg/dL) at Week 26 to baseline. Log(Post-baseline TG) - log(Baseline TG); change from baseline to Week 26 is presented as ratio of Week 26 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 (TG) at Week 26 to Baseline | 0.97 ratio | Standard Error 0.02 |
| Exenatide Twice Daily | Ratio of Triglycerides (TG) at Week 26 to Baseline | 0.97 ratio | Standard Error 0.03 |
Comparison: TG data were logarithm-transformed and the change at Week 26 to baseline, expressed as the ratio, was analyzed using a MMRM ANCOVA model with treatment, baseline TG, country, background OAD, week of visit, and treatment-by-week interaction as fixed effects; and patient and error as random effects.p-value: 0.80795% CI: [0.93, 1.06]Mixed Models Analysis