Exenatide

To compare the change from baseline in HbA1c achieved with exenatide once weekly (EQW) added to titrated basal insulin glargine to placebo added to titrated basal insulin glargine, with or without metformin, after 28 weeks of double-blind treatment. SU= sulfonylurea.

Change in HbA1c from baseline following 30 weeks of therapy (i.e. HbA1c at week 30 minus HbA1c at baseline).

Change in HbA1c from baseline following 30 weeks of therapy (i.e., HbA1c at week 30 minus HbA1c at baseline). Unit of measure is percent of hemoglobin that is glycosylated.

Percentage of patients experiencing treatment-emergent adverse events over 52 weeks

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. Mean event rate = total number of events for all subjects in a treatment regimen / the total number of subject years of exposure for all subjects in that treatment. Standard error = square root of (total number of events / (subject years of exposure)\*\*2).

Change from baseline in HbA1c is reported as adjusted least square (LS) mean values at Week 28. Baseline is defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of study medication. A mixed model with repeated measures (MMRM) analysis was performed, excluding measurements after initiation of rescue medication and study drug discontinuation.

Post-treatment adverse events (AEs) were defined as AEs that started or worsened during the off-treatment period (Safety Follow-up Period), which was defined as the day after the Week 28/early discontinuation (ED) visit to the date of completion of the Safety Follow-up Period. The AESIs recorded were as follows: hematological malignancies, thyroid neoplasms, pancreas neoplasms, aplastic anemia, pancreatitis, pregnancy and pregnancy outcomes (including congenital anomalies).

Change in HbA1c from baseline following 24 weeks of treatment (i.e., HbA1c at week 24 minus HbA1c at week 0)

Change from baseline to endpoint in average heart rate measured over 24 hours by an ambulatory blood pressure monitor.

Patients who experienced specified treatment-emergent antibody status at any point during the study (grouped by maximum titer level experienced)

Number of patients experiencing a potentially immune-related treatment-emergent adverse event at any point during the study

Change in HbA1c from Baseline to Week 24

Change in body weight from baseline (Week 0) after 24 weeks of treatment (i.e., weight at week 24 minus weight at week 0). Body weight measured in kilograms (k).

Evaluate the change in glycemic control as measured by HbA1c from Baseline to Week 12

Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.

Treatment failure is defined as one of the following:1. HbA1c exceeding 9% at any visit after the initial 3 months of treatment (i.e., earliest at Month 6), on the maximally tolerated dose of antidiabetic agents. 2. HbA1c exceeding 7% at 2 consecutive visits 3 months apart, after the initial 6 months of treatment (i.e., earliest at Month 9), on the maximally tolerated dose of antidiabetic agents.

Composite endpoint evaluating effect of treatment on glycemic control and weight

Absolute change in HbA1c from Baseline (Day -3) to Week 30 \[Week 30 - Baseline\]

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

Change in insulin incremental area under the concentration-time curve (ASIiAUC) from baseline to week 20. ASIiAUC is a measure of beta-cell function.

Change in HbA1c from Baseline to the end of each 16-week period. There is one 16-week period of exenatide treatment and one 16-week period of insulin glargine.

Treatment effect on beta-cell function as measured by the ratio of Week 52 arginine-stimulated insulin secretion during a hyperglycemic clamp(specifically, the incremental AUC of insulin with respect to basal value over a 10 min period \[i.e., clamp time 290 min to 300 min\]) to that at baseline (i.e., the ratio is calculated as arginine-stimulated insulin secretion at week 52 divided by arginine-stimulated insulin secretion at baseline \[week -2\]).

Change in HbA1c from Baseline (Visit 3) to study termination at Week 16, and at all study visits in between

Change from Baseline to Week 16 in FSG and glucose measured at different times throughout the day derived from 7-point self-monitored glucose (SMG) profile (glucose measurements before and 2 hours after the start of the morning, midday, and evening meals, and at bedtime)

Visits for this study occur at 6-mo (±2 wk) intervals until exenatide is approved for marketing.

Change in HbA1c from baseline to week 52

Change in HbA1c from Visit 1 to each visit up to open-ended study termination

Change in body weight (kg) from Visit 1 to each visit up to open-ended study termination

Change in fasting plasma glucose from Visit 1 to each visit up to open-ended study termination

Change in lipids from Visit 1 to each visit up to open-ended study termination

Change in body weight from baseline after 24 weeks of treatment (i.e., body weight at week 24 minus body weight at week 0)

Change in HbA1c from Baseline study termination (Week 16)

Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a mixed-effects model for repeated measures (MMRM) between exenatide and placebo.

Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.

Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.

To determine, in healthy subjects, that a single 10 μg dose of exenatide does not differ from placebo in the mean change from predose in 12-lead ECG correct QT (QTc) interval measurements