Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide, long acting release, LAR, Amylin, Lilly
Brief summary
A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release (LAR) on Glucose Control (HbA1c) and Safety in Subjects with Type 2 Diabetes Mellitus Managed with Diet Modification and Exercise and/or Oral Antidiabetic Medications.
Detailed description
This trial is designed to examine the effect of exenatide once weekly compared to exenatide twice daily on glucose control and safety in subjects for at least 30 weeks. The study is also designed to examine glucose control during the transition from exenatide twice daily for 30 weeks to exenatide once weekly. Long-term safety and efficacy will be monitored during the open-ended assessment periods. This study will be conducted in approximately 300 subjects with type 2 diabetes treated with diet modification and exercise alone or in combination with a stable regimen of metformin, SU, thiazolidinedione (TZD), a combination of metformin and SU, a combination of metformin and TZD, or a combination of SU and TZD.
Interventions
DRUGexenatide, long acting release
DRUGexenatide
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has type 2 diabetes mellitus treated with diet modification and exercise alone or in combination with a stable regimen of a combination of metformin, sulphonylureas, and thiazolidinediones for a minimum of 2 months at screening. * Hemoglobin A1c (HbA1c) of 7.1% to 11.0%, inclusive, at screening. * Body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive, at screening. * (For sub-study) Currently participating in open ended assessment period of main study 2993 LAR105
Exclusion criteria
* Has been previously exposed to exenatide (Byetta®), exenatide LAR, or any glucagon-like peptide-1 (GLP-1) analog. * Received any investigational drug or has participated in any type of clinical trial within 30 days prior to screening. * Has been treated, is currently treated, or is expected to require or undergo treatment with any of the following excluded medications: * Alpha glucosidase inhibitor or meglitinide within 30 days of screening; * Insulin within 2 weeks prior to screening or insulin for longer than 1 week within 3 months of screening; * Regular use (\> 14 days) of drugs that directly affect gastrointestinal motility; * Regular use (\> 14 days) of systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary steroids known to have a high rate of systemic absorption; * Regular use (\> 14 days) of medications with addictive potential such as opiates and opioids; * Prescription or over-the-counter weight loss medications within 6 months of screening. * (For sub-study) Subjects will be terminated from study who do not participate in the dual chamber pen substudy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c From Baseline to Week 30 | Day -3, Week 30 | Absolute change in HbA1c from Baseline (Day -3) to Week 30 \[Week 30 - Baseline\] |
| Sub-study Relative Bioavailability of Exenatide When Administered Using the Exenatide Once Weekly Dual Chambered Pen and the Exenatide Once Weekly Single Dose Tray (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose) | Week 22 | Measure by Geometric mean ratio (GMR) of plasma exenatide average steady state concentration Css,avg at Visit 11-14 to Visit 24-27 with 90% confidence interval |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving HbA1c Target of <7% | Week 30 | Percentage of subjects achieving HbA1c target value of \<7% at Week 30. |
| Percentage of Subjects Achieving HbA1c Target of <=6.5% | Week 30 | Percentages of subjects achieving HbA1c target values of \<=6.5% at Week 30. |
| Exenatide LAR Steady State Concentration From Week 29 to Week 30 | Week 29 to Week 30 | Steady-state plasma exenatide concentration over the dosing interval of Week 29 to Week 30 (0-168 hours) was evaluated. Geometric mean for the average steady-state concentration and its 10th and 90th percentiles were reported. |
| Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14 | Day -3, Week 14 | Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14 |
| Sub-study Safety and Tolerability of Exenatide When Administered Using the Once Weekly Single Dose Tray and the Once Weekly Dual (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose) | Week 22 | Measure by geometric mean ratio of the maximum steady state plasma exenatide concentration Css, max at Visit 11-14 to Visit 24-27 with 90% confidence interval and incidence of treatment-emergent injection site adverse events. |
| Change in Body Weight From Baseline to Week 30 | Day -3, Week 30 | Change in body weight from baseline (Day -3) to Week 30 |
| Change in Body Weight From Baseline to Week 364 | Day -3, Week 364 | Change in body weight from baseline (Day -3) to Week 364 |
| Change in Fasting Plasma Glucose From Baseline to Week 30 | Day -3, Week 30 | Change in fasting plasma glucose from baseline (Day -3) to Week 30. |
| Change in Fasting Plasma Glucose From Baseline to Week 364 | Day -3, Week 364 | Change in fasting plasma glucose from baseline (Day -3) to Week 364. |
| Change in Blood Pressure From Baseline to Week 30 | Day -3, Week 30 | Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 30 |
| Percentage of Subjects Achieving HbA1c Target of <=6.0% | Week 30 | Percentage of subjects achieving HbA1c target values of \<=6.0% at Week 30. |
| Change in Total Cholesterol From Baseline to Week 30 | Day -3, Week 30 | Change in total cholesterol from baseline (Day -3) to Week 30. |
| Change in Total Cholesterol From Baseline to Week 364 | Day -3, Week 364 | Change in total cholesterol from baseline (Day -3) to Week 364. |
| Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30 | Day -3, Week 30 | Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 30. |
| Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364 | Day -3, Week 364 | Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 364. |
| Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364 | Day -3, Week 364 | Change in low-density lipoprotein cholesterol (LDL-C) from baseline (Day -3) to Week 364. |
| Ratio of Triglycerides at Week 30 to Baseline | Day -3, Week 30 | Ratio of triglycerides (measured in mg/dL) at Week 30 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline. |
| Ratio of Triglycerides at Week 364 to Baseline | Day -3, Week 364 | Ratio of triglycerides (measured in mg/dL) at Week 364 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline. |
| Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Day 1 to Week 364 | The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia. |
| Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Day 1 to Week 364 | The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia. |
| Change in Blood Pressure From Baseline to Week 364 | Day -3, Week 364 | Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 364 |
| Change in HbA1c From Baseline to Week 364 | Day -3, Week 364 | Absolute change in HbA1c from Baseline (Day -3) to Week 364 |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Once Weekly -> Exenatide Once Weekly Subcutaneous injection of 2 mg exenatide, once a week. | 148 |
| Exenatide Twice Daily -> Exenatide Once Weekly Subcutaneous injection of exenatide, twice a day (5 mcg exenatide per dose for first 4 weeks, then 10 mcg exenatide per dose for 26 weeks) followed by 2 mg exenatide, once a week. | 147 |
| Total | 295 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative | 1 | 4 |
| Overall Study | Adverse Event | 20 | 14 |
| Overall Study | Investigator Decision | 11 | 10 |
| Overall Study | Loss of Glucose Control | 5 | 7 |
| Overall Study | Lost to Follow-up | 13 | 8 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Withdrawal of Consent | 40 | 42 |
Baseline characteristics
| Characteristic | Exenatide Once Weekly -> Exenatide Once Weekly | Exenatide Twice Daily -> Exenatide Once Weekly | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 24 Participants | 50 Participants |
| Age, Categorical Between 18 and 65 years | 122 Participants | 123 Participants | 245 Participants |
| Age, Continuous | 55.2 years STANDARD_DEVIATION 9.72 | 54.9 years STANDARD_DEVIATION 9.63 | 55.0 years STANDARD_DEVIATION 9.66 |
| Background Oral Antidiabetic Agent Diet and Exercise | 21 participants | 22 participants | 43 participants |
| Background Oral Antidiabetic Agent Metformin (MET) | 56 participants | 50 participants | 106 participants |
| Background Oral Antidiabetic Agent MET+SU | 43 participants | 39 participants | 82 participants |
| Background Oral Antidiabetic Agent MET+TZD | 14 participants | 14 participants | 28 participants |
| Background Oral Antidiabetic Agent Sulfonylurea (SU) | 6 participants | 10 participants | 16 participants |
| Background Oral Antidiabetic Agent SU+MET+TZD | 1 participants | 0 participants | 1 participants |
| Background Oral Antidiabetic Agent SU+TZD | 5 participants | 5 participants | 10 participants |
| Background Oral Antidiabetic Agent Thiazolidinediones (TZD) | 2 participants | 7 participants | 9 participants |
| Glycosylated hemoglobin (HbA1c) | 8.3 percentage of total hemoglobin STANDARD_DEVIATION 0.99 | 8.3 percentage of total hemoglobin STANDARD_DEVIATION 1 | 8.3 percentage of total hemoglobin STANDARD_DEVIATION 0.99 |
| Sex: Female, Male Female | 66 Participants | 72 Participants | 138 Participants |
| Sex: Female, Male Male | 82 Participants | 75 Participants | 157 Participants |
| Weight | 101.7 kg STANDARD_DEVIATION 18.76 | 101.9 kg STANDARD_DEVIATION 21.05 | 101.8 kg STANDARD_DEVIATION 19.9 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 124 / 148 | 106 / 145 | 121 / 128 | 122 / 130 | 265 / 278 |
| serious Total, serious adverse events | 8 / 148 | 5 / 145 | 36 / 128 | 29 / 130 | 71 / 278 |
Outcome results
Primary
Change in HbA1c From Baseline to Week 30
Absolute change in HbA1c from Baseline (Day -3) to Week 30 \[Week 30 - Baseline\]
Time frame: Day -3, Week 30
Population: The ITT Population consisted of all randomized subjects who received at least one injection of study medication. Missing data up to Week 30 were imputed using the last observation carried forward (LOCF) approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Week 30 | -1.87 percentage of total hemoglobin | Standard Error 0.082 |
| Exenatide Twice Daily | Change in HbA1c From Baseline to Week 30 | -1.54 percentage of total hemoglobin | Standard Error 0.082 |
Comparison: Superiority of exenatide long-acting release (LAR) once weekly to BYETTA if the upper limit of the 2-sided 95% confidence interval (CI) for treatment difference (LAR minus BYETTA) is less than 0; non-inferiority if this upper limit is less than 0.4%. Power:Assuming 20% dropout rate with 246 subjects will complete the study. This sample size would provide 90% power for non-inferiority test with assumption of greater reduction (0.1%) in LAR and a common standard deviation of 1.2%.p-value: 0.002395% CI: [-0.54, -0.12]ANOVA
Primary
Sub-study Relative Bioavailability of Exenatide When Administered Using the Exenatide Once Weekly Dual Chambered Pen and the Exenatide Once Weekly Single Dose Tray (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)
Measure by Geometric mean ratio (GMR) of plasma exenatide average steady state concentration Css,avg at Visit 11-14 to Visit 24-27 with 90% confidence interval
Time frame: Week 22
Secondary
Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening
The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.
Time frame: Day 1 to Week 364
Population: ITT Population who participated in the 30-week assessment period and not using SU at screening.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Minor hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Twice Daily | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Twice Daily | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Minor hypoglycemic events | 0.02 events per subject-year | Standard Error 0.02 |
| All Treatment | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| All Treatment | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Minor hypoglycemic events | 0.03 events per subject-year | Standard Error 0.009 |
| Exenatide Twice Daily -> Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Minor hypoglycemic events | 0.06 events per subject-year | Standard Error 0.013 |
| Exenatide Twice Daily -> Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening | Minor hypoglycemic events | 0.04 events per subject-year | Standard Error 0.007 |
Secondary
Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening
The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.
Time frame: Day 1 to Week 364
Population: ITT Population who participated in the 30-week assessment period and using SU at screening.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Minor hypoglycemic events | 0.57 events per subject-year | Standard Error 0.139 |
| Exenatide Twice Daily | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Twice Daily | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Minor hypoglycemic events | 0.38 events per subject-year | Standard Error 0.113 |
| All Treatment | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| All Treatment | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Minor hypoglycemic events | 0.49 events per subject-year | Standard Error 0.046 |
| Exenatide Twice Daily -> Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Minor hypoglycemic events | 0.22 events per subject-year | Standard Error 0.029 |
| Exenatide Twice Daily -> Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Major hypoglycemic events | 0.00 events per subject-year | Standard Error 0 |
| Exenatide Once Weekly With SU | Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening | Minor hypoglycemic events | 0.36 events per subject-year | Standard Error 0.026 |
Secondary
Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14
Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14
Time frame: Day -3, Week 14
Population: Evaluable Meal Tolerance Cohort consisted of ITT subjects who participated in the meal tolerance test and had adequate data to allow the reliable assessment of pharmacodynamics. Only subjects with non-missing baseline and Week 14 values were included in analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14 | -95.88 mg/dL | Standard Error 8.42 |
| Exenatide Twice Daily | Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14 | -125.96 mg/dL | Standard Error 8.292 |
Comparison: Analysis: Change in 2h postprandial glucose from baseline (Day -3) to Week 14 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the 2h postprandial glucose as a covariate. Null hypothesis: no difference between treatments in change from baseline 2h postprandial glucose.p-value: 0.012495% CI: [6.88, 53.28]ANCOVA
Secondary
Change in Blood Pressure From Baseline to Week 30
Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 30
Time frame: Day -3, Week 30
Population: ITT Population using observed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 30 | Sitting Systolic Blood Pressure | -4.4 mmHg | Standard Error 1.04 |
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 30 | Sitting Diastolic Blood Pressure | -1.1 mmHg | Standard Error 0.76 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 30 | Sitting Systolic Blood Pressure | -3.8 mmHg | Standard Error 1.28 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 30 | Sitting Diastolic Blood Pressure | -2.3 mmHg | Standard Error 0.83 |
Secondary
Change in Blood Pressure From Baseline to Week 364
Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 364
Time frame: Day -3, Week 364
Population: 7-Year Completer Population using observed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 364 | Sitting Systolic Blood Pressure | 1.3 mmHg | Standard Deviation 16.21 |
| Exenatide Once Weekly | Change in Blood Pressure From Baseline to Week 364 | Sitting Diastolic Blood Pressure | -1.7 mmHg | Standard Deviation 8.87 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 364 | Sitting Systolic Blood Pressure | 1.0 mmHg | Standard Deviation 17.32 |
| Exenatide Twice Daily | Change in Blood Pressure From Baseline to Week 364 | Sitting Diastolic Blood Pressure | -3.6 mmHg | Standard Deviation 9.59 |
| All Treatment | Change in Blood Pressure From Baseline to Week 364 | Sitting Systolic Blood Pressure | 1.2 mmHg | Standard Deviation 16.73 |
| All Treatment | Change in Blood Pressure From Baseline to Week 364 | Sitting Diastolic Blood Pressure | -2.7 mmHg | Standard Deviation 9.26 |
Secondary
Change in Body Weight From Baseline to Week 30
Change in body weight from baseline (Day -3) to Week 30
Time frame: Day -3, Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight From Baseline to Week 30 | -3.67 kg | Standard Error 0.468 |
| Exenatide Twice Daily | Change in Body Weight From Baseline to Week 30 | -3.59 kg | Standard Error 0.468 |
Comparison: Analysis: Change in body weight from baseline (Day -3) to Week 30 was analyzed using an analysis of covariance (ANCOVA) model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the body weight as a covariate. Null hypothesis: no difference between treatments in change from baseline body weight. Power: based on the primary measurement.p-value: 0.891695% CI: [-1.29, 1.12]ANCOVA
Secondary
Change in Body Weight From Baseline to Week 364
Change in body weight from baseline (Day -3) to Week 364
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Body Weight From Baseline to Week 364 | -5.25 kg | 95% Confidence Interval 0.468 |
| Exenatide Twice Daily | Change in Body Weight From Baseline to Week 364 | -2.71 kg | 95% Confidence Interval 0.468 |
| All Treatment | Change in Body Weight From Baseline to Week 364 | -3.87 kg | — |
Secondary
Change in Fasting Plasma Glucose From Baseline to Week 30
Change in fasting plasma glucose from baseline (Day -3) to Week 30.
Time frame: Day -3, Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Plasma Glucose From Baseline to Week 30 | -41.5 mg/dL | Standard Error 2.97 |
| Exenatide Twice Daily | Change in Fasting Plasma Glucose From Baseline to Week 30 | -24.6 mg/dL | Standard Error 2.9 |
Comparison: Analysis: Change in fasting plasma glucose from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the fasting plasma glucose as a covariate. Null hypothesis: no difference between treatments in change from baseline fasting plasma glucose. Power: based on the primary measurement.p-value: <0.000195% CI: [-24.4, -9.4]ANCOVA
Secondary
Change in Fasting Plasma Glucose From Baseline to Week 364
Change in fasting plasma glucose from baseline (Day -3) to Week 364.
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Fasting Plasma Glucose From Baseline to Week 364 | -18.3 mg/dL | 95% Confidence Interval 2.97 |
| Exenatide Twice Daily | Change in Fasting Plasma Glucose From Baseline to Week 364 | -27.7 mg/dL | 95% Confidence Interval 2.9 |
| All Treatment | Change in Fasting Plasma Glucose From Baseline to Week 364 | -23.6 mg/dL | — |
Secondary
Change in HbA1c From Baseline to Week 364
Absolute change in HbA1c from Baseline (Day -3) to Week 364
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the last observation carried forward (LOCF) approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in HbA1c From Baseline to Week 364 | -1.49 percentage of total hemoglobin | 95% Confidence Interval 0.155 |
| Exenatide Twice Daily | Change in HbA1c From Baseline to Week 364 | -1.57 percentage of total hemoglobin | 95% Confidence Interval 0.144 |
| All Treatment | Change in HbA1c From Baseline to Week 364 | -1.53 percentage of total hemoglobin | 95% Confidence Interval 0.115 |
Secondary
Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30
Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 30.
Time frame: Day -3, Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30 | -0.9 mg/dL | Standard Error 0.56 |
| Exenatide Twice Daily | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30 | -1.3 mg/dL | Standard Error 0.57 |
Comparison: Analysis: Change in HDL-C from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the HDL as a covariate. Null hypothesis: no difference between treatments in change from baseline HDL. Power: based on the primary measurement.p-value: 0.561395% CI: [-1, 1.9]ANCOVA
Secondary
Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364
Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 364.
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364 | 2.2 mg/dL | 95% Confidence Interval 0.56 |
| Exenatide Twice Daily | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364 | 3.4 mg/dL | 95% Confidence Interval 0.57 |
| All Treatment | Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364 | 2.8 mg/dL | — |
Secondary
Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364
Change in low-density lipoprotein cholesterol (LDL-C) from baseline (Day -3) to Week 364.
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364 | -13.6 mg/dL | 95% Confidence Interval 0.56 |
| Exenatide Twice Daily | Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364 | -7.5 mg/dL | 95% Confidence Interval 0.57 |
| All Treatment | Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364 | -10.4 mg/dL | — |
Secondary
Change in Total Cholesterol From Baseline to Week 30
Change in total cholesterol from baseline (Day -3) to Week 30.
Time frame: Day -3, Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Week 30 | -11.9 mg/dL | Standard Error 2.29 |
| Exenatide Twice Daily | Change in Total Cholesterol From Baseline to Week 30 | -3.8 mg/dL | Standard Error 2.35 |
Comparison: Analysis: Change in total cholesterol from baseline (Day -3) to Week 30 was analyzed using an ANCOVA model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the total cholesterol as a covariate. Null hypothesis: no difference between treatments in change from baseline total cholesterol. Power: based on the primary measurement.p-value: 0.007795% CI: [-14.1, -2.2]ANCOVA
Secondary
Change in Total Cholesterol From Baseline to Week 364
Change in total cholesterol from baseline (Day -3) to Week 364.
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Change in Total Cholesterol From Baseline to Week 364 | -15.0 mg/dL | 95% Confidence Interval 2.29 |
| Exenatide Twice Daily | Change in Total Cholesterol From Baseline to Week 364 | -4.8 mg/dL | 95% Confidence Interval 2.35 |
| All Treatment | Change in Total Cholesterol From Baseline to Week 364 | -9.6 mg/dL | — |
Secondary
Exenatide LAR Steady State Concentration From Week 29 to Week 30
Steady-state plasma exenatide concentration over the dosing interval of Week 29 to Week 30 (0-168 hours) was evaluated. Geometric mean for the average steady-state concentration and its 10th and 90th percentiles were reported.
Time frame: Week 29 to Week 30
Population: The Pharmacokinetics Population consisted of subjects who received exenatide LAR treatment, and had adequate plasma exenatide concentration-time data to allow for reliable evaluation of exenatide LAR pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Exenatide Once Weekly | Exenatide LAR Steady State Concentration From Week 29 to Week 30 | 300.23 pg/mL |
Secondary
Percentage of Subjects Achieving HbA1c Target of <=6.0%
Percentage of subjects achieving HbA1c target values of \<=6.0% at Week 30.
Time frame: Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c Target of <=6.0% | 23.0 percentage of subjects |
| Exenatide Twice Daily | Percentage of Subjects Achieving HbA1c Target of <=6.0% | 16.3 percentage of subjects |
Comparison: Analysis: Percentages of subjects achieving HbA1c target values of \<=6.0% at Week 30 were compared between treatments using CMH test, in which baseline HbA1c stratum (\<9% or \>=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.p-value: 0.1513Cochran-Mantel-Haenszel
Secondary
Percentage of Subjects Achieving HbA1c Target of <=6.5%
Percentages of subjects achieving HbA1c target values of \<=6.5% at Week 364
Time frame: Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c Target of <=6.5% | 22.4 percentage of subjects |
| Exenatide Twice Daily | Percentage of Subjects Achieving HbA1c Target of <=6.5% | 37.5 percentage of subjects |
| All Treatment | Percentage of Subjects Achieving HbA1c Target of <=6.5% | 30.3 percentage of subjects |
Secondary
Percentage of Subjects Achieving HbA1c Target of <=6.5%
Percentages of subjects achieving HbA1c target values of \<=6.5% at Week 30.
Time frame: Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c Target of <=6.5% | 3.0 percentage of subjects |
| Exenatide Twice Daily | Percentage of Subjects Achieving HbA1c Target of <=6.5% | 16.3 percentage of subjects |
Comparison: Analysis: Percentage of subjects achieving HbA1c target value of \<=6.5% at Week 30 were compared between treatments using CMH test, in which baseline HbA1c stratum (\<9% or \>=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.p-value: 0.2042Cochran-Mantel-Haenszel
Secondary
Percentage of Subjects Achieving HbA1c Target of <7%
Percentages of subjects achieving HbA1c target value of \<7% at Week 364
Time frame: Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c Target of <7% | 41.4 percentage of subjects |
| Exenatide Twice Daily | Percentage of Subjects Achieving HbA1c Target of <7% | 50.0 percentage of subjects |
| All Treatment | Percentage of Subjects Achieving HbA1c Target of <7% | 45.9 percentage of subjects |
Secondary
Percentage of Subjects Achieving HbA1c Target of <7%
Percentage of subjects achieving HbA1c target value of \<7% at Week 30.
Time frame: Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using LOCF for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement. Subjects without post-baseline measurement were categorized as not achieving goal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide Once Weekly | Percentage of Subjects Achieving HbA1c Target of <7% | 70.9 percentage of subjects |
| Exenatide Twice Daily | Percentage of Subjects Achieving HbA1c Target of <7% | 51.0 percentage of subjects |
Comparison: Analysis: Percentages of subjects achieving HbA1c target value of \<7% at Week 30 were compared between treatments using a Cochran-Mantel-Haenszel (CMH) test, in which baseline HbA1c stratum (\<9% or \>=9%) and concomitant SU use at screening served as the stratification factors. Null hypothesis: no difference between treatments in percentage of subjects achieving HbA1c target. Power: based on the primary measurement.p-value: 0.0003Cochran-Mantel-Haenszel
Secondary
Ratio of Triglycerides at Week 30 to Baseline
Ratio of triglycerides (measured in mg/dL) at Week 30 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time frame: Day -3, Week 30
Population: ITT Population. Missing data up to Week 30 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Ratio of Triglycerides at Week 30 to Baseline | 0.85 ratio | Standard Error 0.029 |
| Exenatide Twice Daily | Ratio of Triglycerides at Week 30 to Baseline | 0.89 ratio | Standard Error 0.031 |
Comparison: Analysis: Triglycerides data were logarithm-transformed and the change at Week 30 to baseline (Day -3), expressed as the ratio, was analyzed by an ANCOVA model including treatment, baseline HbA1c stratum (\<9% or \>=9%), and concomitant SU use at screening as factors, and baseline value of the triglycerides as a covariate. Null hypothesis: no difference between treatments in change from baseline triglycerides. Power: based on the primary measurement.p-value: 0.291595% CI: [0.87, 1.04]ANCOVA
Secondary
Ratio of Triglycerides at Week 364 to Baseline
Ratio of triglycerides (measured in mg/dL) at Week 364 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.
Time frame: Day -3, Week 364
Population: 7-Year Completer Population. Missing data up to Week 364 were imputed using the LOCF approach for subjects who had data for at least one scheduled visit (including Early Termination) subsequent to the baseline measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide Once Weekly | Ratio of Triglycerides at Week 364 to Baseline | 0.91 ratio | 95% Confidence Interval 0.029 |
| Exenatide Twice Daily | Ratio of Triglycerides at Week 364 to Baseline | 0.94 ratio | 95% Confidence Interval 0.031 |
| All Treatment | Ratio of Triglycerides at Week 364 to Baseline | 0.93 ratio | — |
Secondary
Sub-study Safety and Tolerability of Exenatide When Administered Using the Once Weekly Single Dose Tray and the Once Weekly Dual (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)
Measure by geometric mean ratio of the maximum steady state plasma exenatide concentration Css, max at Visit 11-14 to Visit 24-27 with 90% confidence interval and incidence of treatment-emergent injection site adverse events.
Time frame: Week 22