Exenatide once weekly

An estimation of β-cell compensatory function, the insulin secretion-sensitivity index (IS-SI) will be derived by applying the concept of the oral disposition index to measurements obtained during the 2-h OGTT and calculated as the index of insulin secretion factored by insulin sensitivity (ΔINS/ΔPG 30 x Matsuda SIOGTT) from the OGTT. A higher score shows improved pancreatic insulin responsiveness relative to resistance.

Absolute change in HbA1c from baseline (Day 1, Visit 3) to Week 28/Study Termination (Visit 11). Hypothesis testing on the primary endpoint followed a serial gated procedure with all tests carried out at a 2-sided significance level of 0.05 to protect the family-wise error rate. These tests were conducted sequentially, and are presented in the statistical analysis section below in the order in which they were performed; each test was the gatekeeper of later tests.

Change from baseline in HbA1c (%) to Week 24 during the controlled assessment period is reported as adjusted least square (LS) mean values. Baseline was defined as the last non-missing assessment (scheduled or unscheduled) on or prior to the first dose of randomized study medication. A mixed model with repeated measures (MMRM) analysis was performed, excluding data collected after initiation of rescue medication or premature discontinuation of study medication.

A controlled assessment period AE was defined as an AE starting on or after day of first dose of study medication up to but not including Week 24 for patients entering the extension period. For patients not entering the extension period, the period was defined up to and including last dose of study medication + 7 days (+ 90 days for serious AEs \[SAEs\] and other clinically significant or related AEs). The Investigator assessed AEs for causal relationship to study drug medication.

Percentage of patients positive for ADAs up to Week 24 for the exenatide treatment group is reported. Baseline was the antibody measurement at Week 0 (Day 1). A negative or missing antibody measurement was considered negative at baseline. High positive = antibody titers ≥ 625, including baseline assessment. Low positive = antibody titers \< 625, including baseline assessment. A patient was said to have treatment-emergent ADA positive at a visit if the antibody test was positive after the first dose of exenatide following a negative or missing antibody measurement, or the titer increased by at least 1 titration category from a detectable measurement prior to first dose of randomized study medication.

The primary efficacy outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary efficacy endpoint is the same as the primary safety endpoint, and the statistical analysis tests the superiority of exenatide against the placebo.

The primary safety outcome variable is defined as the composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke. The number of participants who had an event is reported in the results. The primary safety endpoint is the same as the primary efficacy endpoints, and the statistical analysis tests the non-inferiority of exenatide against placebo.

Change in HbA1c from baseline to the treatment endpoint at Week 26.

The primary endpoint is the percentage of patients achieving HbA1c concentration ≤7.0% with weight loss (≥1.0 kg) at endpoint. The last post-baseline measurement set of both non-missing HbA1c concentration and weight (measured at the same time point, i.e. visit) is used as endpoint value. Patients who do not have a baseline weight measurement, have a protocol violation of baseline HbA1c \<=7.0%, and/or have missing post-baseline measurements for HbA1c concentration and/or weight, are included in the analysis as non-responders regarding the primary objective.

Change in HbA1c from baseline to Week 26.

Change in HbA1c from baseline to endpoint (Week 26).

Change in HbA1c from baseline (Day 1) to Week 24 \[Week 24 - Baseline\].

Percentage of patients achieving HbA1c \<=7% at Week 26 (for patients with baseline HbA1c \>7%).

HbA1c was measured as a percent of total hemoglobin at screening, Baseline, and during treatment on Weeks 4, 8, 12, 16, and 20. Baseline was Day 1, or last measurement prior to first dose of study drug. The Evaluable population was defined as participants who completed study procedures in compliance with the protocol and had adequate exposure to the study drug.

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 and the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. AUC was measured in picograms \* hours per milliliter (pg\*hr/mL). Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y; AUC (0-8h) and (0-tlast) are presented below. Pharmacokinetic (PK) evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] from Day 1 to Week 12 and had reliable PK data.

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 and the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Cmax was measured in picograms per milliliter (pg/mL). Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] from Day 1 to Week 12 for the evaluation of the PK characteristics of plasma exenatide and had reliable PK data. Cmax (0-8h) and (0-tlast) are presented below.

Cohort 1: Blood samples for the assessment of plasma exenatide were collected at time(t) = -15, 60, 90, 120, 180, 240, 360, and 480 minutes relative to study medication injection at time = 0 on Day 1 an the mean is presented below. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Tmax was measured in hours and Tmax (0-8h) and (0-tlast) are presented below. Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements \[not less than (\<) lower limits of quantification (LLOQ)\] and had reliable PK data.

Treatment emergent (TE)=occurs during or after treatment with study drug. Adverse Event (AE)=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Participants experiencing multiple episodes of a given AE are counted once. Injection site AEs: adverse events that existed prior to Day 1 and worsened after the first administration at Day 1, or occurred after the first administration at Day 1 through Week 12, or after Study Termination if considered by investigator to be clinically significant.

Concomitant medications are defined as those medications received on or after the date of the first injection on Day 1, including prior medications that continued past Day 1 and new concomitant medications. Participants may be counted in more than one medication class and no more than once in each class. Categories by Anatomical Therapeutic Chemical (ATC) classification using the World Health Organization (WHO) Drug Dictionary version C1, 01 March 2009. As per protocol, all participants in Cohort 1 could receive up to 2 anti-emetic medications approximately 30 minutes prior to the exenatide.

In Cohort 1, sitting blood pressures were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-11 (Visits 3-13), Week 12 (Visit 14), and at early termination. Blood pressures (diastolic and systolic) were measured in millimeters of mercury (mmHg). In Cohort 2, sitting blood pressures were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-10 (Visits 3-12), Week 11 (Visit 15), Week 12 (Visit 16) and at early termination. Baseline was defined as last measurement prior to first injection of study drug.

In Cohort 1, sitting heart rates were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-11 (Visits 3-13), Week 12 (Visit 14), and at early termination. Heart rate was measured in beats per minute (bpm). In Cohort 2, sitting heart rates were obtained at Screening (Visit 1), Day 1 (Visit 2), Weeks 1-10 (Visits 3-12), Week 11 (Visit 15), Week 12 (Visit 16) and at early termination. Baseline was defined as last measurement prior to first injection of study drug.

Abbreviations: Upper Limit of Normal (ULN); milligram per deciliter (mg/dL); units per liter (U/L); micro liters (µL); creatine kinase (CK); gamma-glutamyltransferase (G-GT). Normal ranges = Hematocrit: 40.6-52.3% (male), 35.3-47.0 (female); Platelets 155-361\*10\^3/µL(male/female); Calcium: 8.6-10.4 mg/dL (male/female); CK: 43-350 U/L (male), 28-207 U/L (female); G-GT: 7-62 U/L (male/female); Glucose 73-105 mg/dL (male/female); Lipase 14-70 U/L (male/female); Uric acid: 3.5-7.8 mg/dL (male), 2.3-5.9 mg/dL (female). Blood samples for laboratories were collected at screening, Day 1, Weeks 4, 8, 12 or early termination. Value for potential clinical importance is presented in each category presented below.

Serum titers of antibodies to exenatide were evaluated using a validated enzyme-linked immunosorbent assay (Covance Method No. ELISA-0308). Positive antibody to exenatide titer: observed at the indicated visit following a negative or missing titer at baseline, or a positive titer that has increased by at least 3 dilutions at the indicated visit from a detectable baseline. Baseline=Day 1. Negative titers were assigned a value of 1 in order to calculate geometric mean. Geometric mean of reportable titers, by study week, are presented below.

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. AUC was measured in picograms \* hours per milliliter (pg\*hr/mL). Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y; AUC (0-6h) measured at Week 10, AUC (0-168h) steady state measured between Weeks 10 and 11, and AUC (0-tlast) for time interval between Weeks 10 and 12 (approximately336 hours) are presented below. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. Cave(0-168h) and Cave(0-tlast) was the time-weighted mean concentration over the sampling period from time x to time y corresponding to AUC (0-168h), and AUC (0-tlast), respectively. Cave was measured in picograms per milliliter (pg/mL). Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. Cmax was measured in pg/mL. Exenatide was measured using a validated enzyme-linked immunosorbent assay (ELISA). Cmax summarized at 0-6 h at Week 10, 0-168 h at Weeks 10-11, and 0-tlast at Weeks 10-12. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.

Cohort 2: Blood samples for the assessment of plasma exenatide were collected on Day 1, Weeks 2, 4, 6, 8, and 10. At Week 10, blood samples were collected at time = -15, 60, 90, 120, 180, 240, and 360 minutes relative to study medication injection at time = 0. Tmax was measured in hours (h). Exenatide was measured using a validated ELISA. Tmax summarized at 0-6 h at Week 10, 0-168 h at Weeks 10-11, and 0-tlast at Weeks 10-12. PK evaluable population consisted of all ITT participants who had at least 4 detectable plasma exenatide measurements (not \< LLOQ) from Day 1 to Week 12 and had reliable PK data.