Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes; exenatide once weekly; Byetta; glargine; Lantus; Amylin; Lilly
Brief summary
The objectives of this clinical trial are to compare the effects of exenatide once weekly and insulin glargine on blood glucose control, body weight, lipids, safety, and tolerability.
Interventions
subcutaneous injection, 2.0mg, once a week;
DRUGinsulin glargine
subcutaneous injection, titrated to achieve fasting serum glucose target, once a day
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
* present with type 2 diabetes mellitus * HbA1c between 7.1% and 11.0% inclusive * body mass index (BMI) of \>18kg/m2 and \<35kg/m2, inclusive * treated with a stable dose regimen of either of biguanide (BG) alone, BG + thiazolidinedione (TZD), BG + sulfonylurea (SU), or BG + TZD + SU for 90 days prior to study start
Exclusion criteria
* Have received chronic (\>14 consecutive days) systemic adrenocorticosteroid therapy by oral, intravenous, or intramuscular route or intraarticular steroid injection within 4 weeks prior to study start. * Have been treated with drugs that promote weight loss within 90 days prior to study start. * Have been treated with drugs that directly affect gastrointestinal motility for \> 21 consecutive days within 90 days prior to study start. * Have had prior exposure to exenatide BID or QW or participated in the clinical trial of exenatide BID or QW (including the case that the study drug was not administered). * Have been treated for \>2 consecutive weeks with any of the following excluded medications within 90 days prior to study start: Insulin, Dipeptidyl peptidase-4 (DPP-4) inhibitors, GLP-1 analogs * Have received treatment within 30 days prior to study start drug that has not received regulatory approval for any indication. * Are currently enrolled in any other clinical study or participated in and completed the clinical study within 30 days prior to study start. * Have donated blood within 30 days prior to study start.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in HbA1c from baseline to endpoint (Week 26). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving HbA1c<=6.5% | Baseline, Week 26 | Percentage of subjects achieving HbA1c \<=6.5% (for subjects with HbA1c \>6.5% at baseline) |
| Change in Fasting Serum Glucose (FSG) From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in FSG (centralized measurement) from baseline to endpoint (Week 26) |
| Change in Body Weight From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in Body Weight from baseline to endpoint (Week 26) |
| Change in Total Cholesterol From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in Total Cholesterol from baseline to endpoint (Week 26) |
| Percentage of Subjects Achieving HbA1c<=7% | Baseline, Week 26 | Percentage of subjects achieving HbA1c \<=7.0% (for subjects with HbA1c \>7% at baseline) |
| Ratio of Fasting Triglycerides at Endpoint (Week 26) to Baseline | Baseline, Week 26 | Ratio of Triglycerides (measured in mg/dL) at endpoint (Week 26) to Baseline. Log(Postbaseline Triglycerides) - log(Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline. |
| Change in Blood Pressure From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in Blood Pressure from baseline to endpoint (Week 26) |
| Assessment on Event Rate of Treatment-emergent Major Hypoglycemic Events | Baseline to Week 26 | Major confirmed hypoglycemia was defined as (1) any event accompanying symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure but resolved promptly in response to administration of glucagon or (2) glucose, or documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) requiring assistance because of severe impairment in consciousness or motor activity whether or not symptoms of hypoglycemia were felt by the patient. 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 postbaseline visit date - baseline visit date. Mean and SE were then derived from FAS. |
| Assessment on Event Rate of Treatment-emergent Minor Hypoglycemic Events | Baseline to Week 26 | Minor confirmed hypoglycemia was defined as any event a patient felt that he or she was experiencing a sign or symptom associated with hypoglycemia that resolved by self-treatment or on its own, and a concurrent self-monitoring fingerstick 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 postbaseline visit date - baseline visit date. Mean and SE were then derived from FAS. |
| Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Endpoint (Week 26) | Baseline, Week 26 | Change in HDL-C from baseline to endpoint (Week 26) |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly Subcutaneous injection, 2.0mg, once a week. | 215 |
| Insulin Glargine Subcutaneous injection, titrated to achieve fasting serum glucose target, once a day | 212 |
| Total | 427 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 6 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Loss Glucose Control | 4 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Sponsor Decision | 0 | 1 |
| Overall Study | Subject Decision | 2 | 1 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly | Insulin Glargine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 55 Participants | 56 Participants | 111 Participants |
| Age, Categorical Between 18 and 65 years | 160 Participants | 156 Participants | 316 Participants |
| Age, Continuous | 57.1 years STANDARD_DEVIATION 10.44 | 56.4 years STANDARD_DEVIATION 11.16 | 56.8 years STANDARD_DEVIATION 10.8 |
| Background Oral Antidiabetic Agent (OAD) BG+Thiazolidine Derivative (TZD) | 70 participants | 70 participants | 140 participants |
| Background Oral Antidiabetic Agent (OAD) Biguanide (BG) | 145 participants | 142 participants | 287 participants |
| Glycosylated hemoglobin (HbA1c) | 8.51 percentage of total hemoglobin STANDARD_DEVIATION 0.823 | 8.50 percentage of total hemoglobin STANDARD_DEVIATION 0.791 | 8.50 percentage of total hemoglobin STANDARD_DEVIATION 0.806 |
| Sex: Female, Male Female | 73 Participants | 64 Participants | 137 Participants |
| Sex: Female, Male Male | 142 Participants | 148 Participants | 290 Participants |
| Weight | 69.95 kg STANDARD_DEVIATION 13.246 | 71.03 kg STANDARD_DEVIATION 13.932 | 70.49 kg STANDARD_DEVIATION 13.586 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 145 / 215 | 65 / 212 |
| serious Total, serious adverse events | 6 / 215 | 5 / 212 |
Outcome results
Primary
Change in HbA1c From Baseline to Endpoint (Week 26)
Change in HbA1c from baseline to endpoint (Week 26).
Time frame: Baseline, Week 26
Population: Statistical analysis of this study was performed for the full analysis set (FAS). FAS consisted of randomized patients who received administration of the study drug at least once and had measurement values after administration. Missing data at endpoint was imputed using last observation carried forward (LOCF) approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Endpoint (Week 26) | -1.11 percentage of total hemoglobin | Standard Error 0.06 |
| Insulin Glargine | Change in HbA1c From Baseline to Endpoint (Week 26) | -0.68 percentage of total hemoglobin | Standard Error 0.06 |
Comparison: The expected changes in HbA1c from baseline were considered to be the same between the groups, and the common standard deviation assumed to be 1.2%. Assuming a type I error of 0.025 (one-sided), a power of 0.9 and a noninferiority margin of 0.4%, 191 subjects per group would be necessary to confirm the noninferiority by the two-sample t-test. When the proportion of the subjects missing post-baseline data was assumed to be 10%, the target number of subjects were 420 in total (210 subjects/group).p-value: <0.00195% CI: [-0.59, -0.26]ANCOVA
Secondary
Assessment on Event Rate of Treatment-emergent Major Hypoglycemic Events
Major confirmed hypoglycemia was defined as (1) any event accompanying symptoms consistent with hypoglycemia that resulted in loss of consciousness or seizure but resolved promptly in response to administration of glucagon or (2) glucose, or documented hypoglycemia (blood glucose \<3.0 mmol/L \[54 mg/dL\]) requiring assistance because of severe impairment in consciousness or motor activity whether or not symptoms of hypoglycemia were felt by the patient. 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 postbaseline visit date - baseline visit date. Mean and SE were then derived from FAS.
Time frame: Baseline to Week 26
Population: FAS Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Major Hypoglycemic Events | 0.00 events per subject-year | Standard Error 0 |
| Insulin Glargine | Assessment on Event Rate of Treatment-emergent Major Hypoglycemic Events | 0.00 events per subject-year | Standard Error 0 |
Secondary
Assessment on Event Rate of Treatment-emergent Minor Hypoglycemic Events
Minor confirmed hypoglycemia was defined as any event a patient felt that he or she was experiencing a sign or symptom associated with hypoglycemia that resolved by self-treatment or on its own, and a concurrent self-monitoring fingerstick 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 postbaseline visit date - baseline visit date. Mean and SE were then derived from FAS.
Time frame: Baseline to Week 26
Population: FAS Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Minor Hypoglycemic Events | 0.01 events per subject-year | Standard Error 0.01 |
| Insulin Glargine | Assessment on Event Rate of Treatment-emergent Minor Hypoglycemic Events | 0.16 events per subject-year | Standard Error 0.13 |
Secondary
Change in Blood Pressure From Baseline to Endpoint (Week 26)
Change in Blood Pressure from baseline to endpoint (Week 26)
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Endpoint (Week 26) | Systolic Blood Pressure | -4.5 mmHg | Standard Deviation 14.04 |
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Endpoint (Week 26) | Diastolic Blood Pressure | -1.1 mmHg | Standard Deviation 9.25 |
| Insulin Glargine | Change in Blood Pressure From Baseline to Endpoint (Week 26) | Systolic Blood Pressure | -2.6 mmHg | Standard Deviation 14.29 |
| Insulin Glargine | Change in Blood Pressure From Baseline to Endpoint (Week 26) | Diastolic Blood Pressure | -2.5 mmHg | Standard Deviation 8.88 |
Secondary
Change in Body Weight From Baseline to Endpoint (Week 26)
Change in Body Weight from baseline to endpoint (Week 26)
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight From Baseline to Endpoint (Week 26) | -1.67 kg | Standard Error 0.17 |
| Insulin Glargine | Change in Body Weight From Baseline to Endpoint (Week 26) | 0.34 kg | Standard Error 0.17 |
Comparison: Change in body weight from baseline to endpoint was analyzed using a LOCF ANCOVA model with treatment, background OAD, and presence/absence of pretreatment with SU as factors and baseline body weight as a covariate.p-value: <0.00195% CI: [-2.46, -1.56]ANCOVA
Secondary
Change in Fasting Serum Glucose (FSG) From Baseline to Endpoint (Week 26)
Change in FSG (centralized measurement) from baseline to endpoint (Week 26)
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Serum Glucose (FSG) From Baseline to Endpoint (Week 26) | -46.09 mg/dL | Standard Error 2.4 |
| Insulin Glargine | Change in Fasting Serum Glucose (FSG) From Baseline to Endpoint (Week 26) | -40.82 mg/dL | Standard Error 2.39 |
Comparison: Change in FSG from baseline to endpoint was analyzed using a LOCF ANCOVA model with treatment, background OAD, and presence/absence of pretreatment with SU as factors and baseline FSG as a covariate.p-value: 0.10395% CI: [-11.62, 1.07]ANCOVA
Secondary
Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Endpoint (Week 26)
Change in HDL-C from baseline to endpoint (Week 26)
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Endpoint (Week 26) | -0.99 mg/dL | Standard Error 0.52 |
| Insulin Glargine | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Endpoint (Week 26) | -0.71 mg/dL | Standard Error 0.51 |
Comparison: Change in HDL-C from baseline to endpoint was analyzed using a LOCF ANCOVA model with treatment, background OAD, and presence/absence of pre-treatment with SU as factors and baseline HDL-C as a covariate.p-value: 0.68995% CI: [-1.64, 1.09]ANCOVA
Secondary
Change in Total Cholesterol From Baseline to Endpoint (Week 26)
Change in Total Cholesterol from baseline to endpoint (Week 26)
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Endpoint (Week 26) | -14.21 mg/dL | Standard Error 1.67 |
| Insulin Glargine | Change in Total Cholesterol From Baseline to Endpoint (Week 26) | -6.32 mg/dL | Standard Error 1.67 |
Comparison: Change in total cholesterol from baseline to endpoint was analyzed using a LOCF ANCOVA model with treatment, background OAD, and presence/absence of pretreatment with SU as factors and baseline total cholesterol as a covariate.p-value: <0.00195% CI: [-12.33, -3.45]ANCOVA
Secondary
Percentage of Subjects Achieving HbA1c<=6.5%
Percentage of subjects achieving HbA1c \<=6.5% (for subjects with HbA1c \>6.5% at baseline)
Time frame: Baseline, Week 26
Population: FAS Population. Only subjects with baseline HbA1c \> target were included in calculation. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c<=6.5% | 20.6 percentage of subjects |
| Insulin Glargine | Percentage of Subjects Achieving HbA1c<=6.5% | 4.2 percentage of subjects |
Comparison: Percentage of subjects achieving HbA1c\<=6.5% at endpoint were compared between treatments using a CMH test, in which background OAD and presence/absence of pretreatment with SU served as the stratification factors.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Percentage of Subjects Achieving HbA1c<=7%
Percentage of subjects achieving HbA1c \<=7.0% (for subjects with HbA1c \>7% at baseline)
Time frame: Baseline, Week 26
Population: FAS Population. Only subjects with baseline HbA1c \> target were included in calculation. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c<=7% | 42.2 percentage of subjects |
| Insulin Glargine | Percentage of Subjects Achieving HbA1c<=7% | 21.0 percentage of subjects |
Comparison: Percentage of subjects achieving HbA1c\<=7% at endpoint were compared between treatments using a Cochran-Mantel-Haenszel (CMH) test, in which background OAD and presence/absence of pretreatment with SU served as the stratification factors.p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Ratio of Fasting Triglycerides at Endpoint (Week 26) to Baseline
Ratio of Triglycerides (measured in mg/dL) at endpoint (Week 26) to Baseline. Log(Postbaseline Triglycerides) - log(Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time frame: Baseline, Week 26
Population: FAS Population. Missing data at endpoint was imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Ratio of Fasting Triglycerides at Endpoint (Week 26) to Baseline | 1.00 ratio | Standard Error 1.02 |
| Insulin Glargine | Ratio of Fasting Triglycerides at Endpoint (Week 26) to Baseline | 1.00 ratio | Standard Error 1.02 |
Comparison: Triglycerides data were logarithm-transformed and the change at endpoint to baseline, expressed as the ratio, was analyzed using a LOCF ANCOVA model with treatment, background OAD, and presence/absence of pretreatment with SU as factors and baseline triglycerides as a covariate.p-value: 0.9995% CI: [0.94, 1.06]ANCOVA