Type 2 Diabetes Mellitus
Conditions
Keywords
diabetes, exenatide once weekly, Byetta, Amylin, Lilly
Brief summary
This study is designed to evaluate the pharmacokinetics, tolerability, and safety of exenatide once weekly suspension in both healthy subjects and in subjects with type 2 diabetes. The study will also evaluate efficacy in the type 2 diabetes patients. Development of this exenatide once weekly presentation would eliminate the need to reconstitute the product prior to use.
Interventions
subcutaneous injection, 10.0 mg, single injection
OTHERPlacebo
subcutaneous injection, volume equivalent to Cohort 2 experimental intervention, once a week for 12 weeks
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Cohort 1: * Is 19 to 65 years old * Has a body mass index (BMI) of 23 kg/m2 to 35 kg/m2, inclusive, at study start Cohort 2: * Is 19 to 75 years old * Has been diagnosed with type 2 diabetes mellitus * Has HbA1c of 7.1% to 10.0%, inclusive, at study start * Has a body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive, at study start * Has been treated with diet and exercise alone or with a stable regimen of metformin, a TZD, or a combination of metformin and a TZD, for a minimum of 2 months prior to study start * Either is not treated with or has been on a stable treatment regimen with any of the following medications for a minimum of 2 months prior to study start: * Hormone replacement therapy (female subjects) * Oral contraceptives (female subjects) * Antihypertensive agents * Lipid-lowering agents * Thyroid replacement therapy * Antidepressant agents
Exclusion criteria
Cohort 1: * Has a personal history of diabetes mellitus (including impaired glucose tolerance, impaired fasting glucose, or gestational diabetes) * Has received any investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is greater) prior to study start * Has ever been exposed to exenatide (BYETTA, exenatide once weekly, or any other formulation of exenatide) or any GLP 1 analog Cohort 2: * Has received any investigational drug within 30 days (or 5 half-lives of the investigational drug, whichever is greater) prior to study start * Has ever been exposed to exenatide (BYETTA, exenatide once weekly, or any other formulation of exenatide) or any GLP 1 analog * Has been treated, is currently being treated, or is expected to require or undergo treatment with any of the following treatment-excluded medications: * Any DPP-4 inhibitor or sulfonylurea (SU) within 3 months prior to study start * Alpha glucosidase inhibitor, meglitinide, nateglinide, or pramlintide (SYMLIN®) within 30 days prior to study start * Insulin within 2 weeks prior to study start or for more than 1 week within 3 months prior to study start * Systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary (including ADVAIR®) steroids known to have a high rate of systemic absorption * Prescription or over-the-counter weight loss medications within 3 months prior to study start
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population | Week 10, Weeks 10-11, Weeks 10-12 | 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. |
| Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population | Day 1 to Week 12 | 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. |
| Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Day 1 to Week 12 | 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. |
| Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Day 1 to Week 12 | 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. |
| Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Week 10-11; Weeks 10 - 12 | 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. |
| Average Exenatide Concentration (Cave) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Week 10 - Week 11; Week 10 - Week 12 | 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. |
| Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Week 10, Weeks 10-11, Weeks 10-12 | 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. |
| Area Under the Curve (AUC) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Day 1, Week 12 | 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. |
| Maximum Concentration (Cmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Day 1, Week 12 | 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. |
| Time to Maximum Concentration (Tmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Day 1, Week 12 | 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. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Day 1 to Week12 | 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. |
| Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population | Day 1 to 12 weeks | 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. |
| Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Day 1 to Week 12 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Exenatide Concentration (Cave) of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Day 1 to Week 1 | 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. At all visits following the single dose, a single blood sample was collected for assessment of exenatide concentrations. Cave(0-168h) was the time-weighted mean concentration over the sampling period from time x to time y corresponding to AUC (0-168h) and 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 and had reliable PK data. |
| Least Square Mean Change From Baseline in Hemoglobin A1c (HbA1c) to Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Day 1 to Week 12 | HbA1c was measured as a percent of hemoglobin at screening, Day 1, Weeks 4, 8, 12 or early termination. Last observation carried forward (LOCF) was applied to estimate missing values at post baseline timepoints. Baseline=Day 1, last measurement prior to first dose of study drug. |
| Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Week 12 | HbA1c was measured as a percent of hemoglobin at screening, Day 1, Weeks 4, 8, 12 or early termination. LOCF was applied to estimate missing values at post baseline timepoints. Baseline=Day 1, last measurement prior to first dose of study drug. |
| Mean Change From Baseline at Week 12 in Body Weight in Participants With Diabetes (Cohort 2) in the ITT Population | Baseline, Week 12 | Body weight was measured in kilograms (kg). Baseline was Day 1, last measurement prior to first dose of study drug. Body weight was measured at screening, Day 1, Weeks 4, 8, 12 or early termination and the LOCF approach was applied to estimate missing value at each post baseline timepoint. |
| Mean Change From Baseline at Week 12 in Fasting Plasma Glucose in Participants With Diabetes (Cohort 2) for the ITT Population | Baseline, Week 12 | Baseline was the last measurement at the screening visit. Fasting plasma glucose (FPG) was measured at screening, Day 1, Weeks 2, 4, 6, 8, 12, or early termination and reported in milligrams per deciliter (mg/dL). |
| AUC (0 Hour to 168 Hour) for 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Day 1 to Week 1 | 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. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. AUC (0-168 h) data represents average concentration rather than maximum concentration. Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y and measured in pg\*h/mL. 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. |
Countries
United States
Participant flow
Recruitment details
Healthy participants were enrolled in Cohort 1 while participants with type 2 diabetes mellitus were enrolled in Cohort 2.
Pre-assignment details
Enrolled participants in Cohort 1 were treated on Day 1 only. Enrolled participants who were in Cohort 2 were randomized to one of 2 treatment arms (exenatide or placebo) and were treated for 12 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Exenatide 10 mg A single 10-mg dose of exenatide once weekly suspension was given to healthy participants via 3 subcutaneous (SC) injections at Day 1. At the discretion of the investigator, participants could receive up to 2 anti-emetic medications approximately 30 minutes prior to the exenatide once weekly suspension dose. | 30 |
| Cohort 2 Exenatide 2 mg On Day 1, participants with type 2 diabetes mellitus treated with diet and exercise alone or with a stable regimen of metformin, a thiazolidinedione (TZD), or a combination of metformin or a TZD were randomized to receive weekly injections of 2 mg exenatide suspension for 12 weeks. Study medication was administered weekly. | 23 |
| Cohort 2 Placebo On Day 1, participants with type 2 diabetes mellitus treated with diet and exercise alone or with a stable regimen of metformin, a thiazolidinedione (TZD), or a combination of metformin or a TZD were randomized to receive weekly injections of medium-chain triglycerides (MCT)-diluent placebo for 12 weeks. Study medication was administered weekly from Visit 2 (Day 1) to Visit 15 (Week 11). | 12 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1 Exenatide 10 mg | Cohort 2 Exenatide 2 mg | Cohort 2 Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 41.2 years STANDARD_DEVIATION 14.4 | 52.7 years STANDARD_DEVIATION 11.6 | 52.0 years STANDARD_DEVIATION 9.3 | 52.4 years STANDARD_DEVIATION 10.7 |
| Body Mass Index (BMI) | 28.5 kg/m^2 STANDARD_DEVIATION 3.5 | 35.3 kg/m^2 STANDARD_DEVIATION 6.7 | 34.9 kg/m^2 STANDARD_DEVIATION 4.9 | 35.1 kg/m^2 STANDARD_DEVIATION 6.1 |
| Body Weight | 85.9 kilograms STANDARD_DEVIATION 15.5 | 104.9 kilograms STANDARD_DEVIATION 23.2 | 104.4 kilograms STANDARD_DEVIATION 20.3 | 104.7 kilograms STANDARD_DEVIATION 22 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Black | 3 participants | 1 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 23 participants | 19 participants | 11 participants | 53 participants |
| Race/Ethnicity, Customized Hispanic | 3 participants | 2 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized Native American | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 30 participants | 23 participants | 12 participants | 65 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 2 Participants | 23 Participants |
| Sex: Female, Male Male | 18 Participants | 14 Participants | 10 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 30 | 22 / 23 | 9 / 12 |
| serious Total, serious adverse events | 0 / 30 | 0 / 23 | 1 / 12 |
Outcome results
Primary
Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2
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.
Time frame: Day 1 to Week 12
Population: Only participants who received exenatide were analyzed (no placebo-treated participants were included). N=number of participants in each treatment at each visit and n= number of participants with reportable titers at the visit. Last visit=last visit with reportable titers.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 2, N=30, 23; n=4, 1 | 25.0 Reportable Titers | Standard Error 0 |
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 4, N=30, 23; n=14, 10 | 394.6 Reportable Titers | Standard Error 204.4 |
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 6, N=30, 23; n=0, 15 | NA Reportable Titers | — |
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 8, N=29, 23; n=22,15 | 300.7 Reportable Titers | Standard Error 118 |
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 10, N=29, 23; n=0,15 | NA Reportable Titers | — |
| Cohort 1 Exenatide 10 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Last visit, N=30, 23; n=20, 15 | 202.6 Reportable Titers | Standard Error 63 |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 10, N=29, 23; n=0,15 | 453.0 Reportable Titers | Standard Error 190.9 |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 2, N=30, 23; n=4, 1 | 25.0 Reportable Titers | — |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 8, N=29, 23; n=22,15 | 561.4 Reportable Titers | Standard Error 186.4 |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 4, N=30, 23; n=14, 10 | 202.6 Reportable Titers | Standard Error 109.2 |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Last visit, N=30, 23; n=20, 15 | 625.0 Reportable Titers | Standard Error 294.5 |
| Cohort 2 Exenatide 2 mg | Antibody Titers for Participants With Treatment Emergent Positive Antibodies to Exenatide in Participants Who Received Exenatide in Cohorts 1 and 2 | Week 6, N=30, 23; n=0, 15 | 295.9 Reportable Titers | Standard Error 129.9 |
Primary
Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population
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.
Time frame: Week 10-11; Weeks 10 - 12
Population: PK evaluable population was analyzed. In categories below, n = number of ITT participants with PK evaluable data. Note: Placebo-treated participants not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | AUC (0-6h) at Week 10, n=18 | 1535.3 pg*hr/mL | Standard Error 232.4 |
| Cohort 1 Exenatide 10 mg | Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | AUC (0-168h) at Weeks 10-11, n=18 | 49100.2 pg*hr/mL | Standard Error 6796.56 |
| Cohort 1 Exenatide 10 mg | Area Under the Curve (AUC) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | AUC (0-tlast) at Weeks 10-12, n=17 | 101615.0 pg*hr/mL | Standard Error 12927.42 |
Primary
Area Under the Curve (AUC) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population
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.
Time frame: Day 1, Week 12
Population: PK evaluable population was analyzed. n in categories below = number of ITT participants with PK evaluable data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Area Under the Curve (AUC) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | AUC (0-8h), n=30 | 125.6 pg*h/mL | Standard Error 41.16 |
| Cohort 1 Exenatide 10 mg | Area Under the Curve (AUC) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | AUC (0-Week 12), n=30 | 147220.2 pg*h/mL | Standard Error 24000.04 |
Primary
Average Exenatide Concentration (Cave) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population
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.
Time frame: Week 10 - Week 11; Week 10 - Week 12
Population: PK evaluable population was analyzed. In categories below, n = number of ITT participants with PK evaluable data. Note: Placebo-treated participants not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Average Exenatide Concentration (Cave) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Cave at Weeks 10-11; n=18 | 292.7 pg/mL | Standard Error 40.52 |
| Cohort 1 Exenatide 10 mg | Average Exenatide Concentration (Cave) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Cave at Weeks 10-12; n=17 | 302.4 pg/mL | Standard Error 38.47 |
Primary
Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population
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.
Time frame: Week 10, Weeks 10-11, Weeks 10-12
Population: PK evaluable population was analyzed. In categories below, n = number of ITT participants with PK evaluable data. Note: Placebo-treated participants not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Cmax at 0-6 h Week 10; n=18 | 304.9 pg/mL | Standard Error 47.39 |
| Cohort 1 Exenatide 10 mg | Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Cmax at 0-168 h Weeks 10=11; n=18 | 362.6 pg/mL | Standard Error 50.86 |
| Cohort 1 Exenatide 10 mg | Maximum Concentration (Cmax) for 2 mg Exenatide (Cohort 2) in Participants With Diabetes in the Pharmacokinetic Evaluable Population | Cmax at 0-tlast Weeks 10-12; n=17 | 410.5 pg/mL | Standard Error 53.27 |
Primary
Maximum Concentration (Cmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population
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.
Time frame: Day 1, Week 12
Population: PK evaluable population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Maximum Concentration (Cmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Cmax 0 hour to 8 hours | 34.9 pg/mL | Standard Error 8.33 |
| Cohort 1 Exenatide 10 mg | Maximum Concentration (Cmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Cmax 0 hour to Week 12 | 331.2 pg/mL | Standard Error 46.9 |
Primary
Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population
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.
Time frame: Day 1 to Week 12
Population: ITT population included all participants treated with at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Diastolic Blood Pressure | 6.2 mmHg | Standard Deviation 7.05 |
| Cohort 1 Exenatide 10 mg | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Systolic Blood Pressure | -1.4 mmHg | Standard Deviation 9.59 |
| Cohort 2 Exenatide 2 mg | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Diastolic Blood Pressure | 4.6 mmHg | Standard Deviation 8.81 |
| Cohort 2 Exenatide 2 mg | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Systolic Blood Pressure | -8.4 mmHg | Standard Deviation 14.15 |
| Cohort 2 Placebo | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Diastolic Blood Pressure | 6.8 mmHg | Standard Deviation 7.81 |
| Cohort 2 Placebo | Mean Change From Baseline to End of Study in Sitting Diastolic and Systolic Blood Pressure in Cohorts 1 and 2 in ITT Population | Systolic Blood Pressure | -1.7 mmHg | Standard Deviation 12.47 |
Primary
Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population
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.
Time frame: Day 1 to Week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population | -7.5 bpm | Standard Deviation 9.38 |
| Cohort 2 Exenatide 2 mg | Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population | -5.4 bpm | Standard Deviation 8.1 |
| Cohort 2 Placebo | Mean Change From Baseline to End of Study in Sitting Heart Rate in Cohorts 1 and 2 in ITT Population | -9.1 bpm | Standard Deviation 7.03 |
Primary
Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population
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.
Time frame: Day 1 to 12 weeks
Population: ITT population included all participants treated with at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 Exenatide 10 mg | Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population | 30 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population | 21 participants |
| Cohort 2 Placebo | Number of Participants With Concomitant Medications in Cohort 1 and Cohort 2 in ITT Population | 11 participants |
Primary
Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population
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.
Time frame: Day 1 to Week 12
Population: ITT population included all participants treated with at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Platelets high <75 to >500*10^3/µ/L | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Calcium high <8 to >11 mg/dL | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Uric Acid high >8.0 mg/dL | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Glucose low <50 to > 450 mg/dL | 1 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Hematocrit low <36% | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Lipase high >3*ULN in U/L | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | G-GT high >3*ULN in U/L | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | CK high >3*ULN | 1 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Lipase high >3*ULN in U/L | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Hematocrit low <36% | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Calcium high <8 to >11 mg/dL | 1 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | CK high >3*ULN | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | G-GT high >3*ULN in U/L | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Glucose low <50 to > 450 mg/dL | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Uric Acid high >8.0 mg/dL | 1 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Platelets high <75 to >500*10^3/µ/L | 1 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Glucose low <50 to > 450 mg/dL | 0 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Uric Acid high >8.0 mg/dL | 0 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Hematocrit low <36% | 1 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Platelets high <75 to >500*10^3/µ/L | 0 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | CK high >3*ULN | 0 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Calcium high <8 to >11 mg/dL | 0 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | Lipase high >3*ULN in U/L | 1 participants |
| Cohort 2 Placebo | Number of Participants With Hematology and Serum Chemistry Laboratory Values of Potential Clinical Importance in Cohorts 1 and 2 in ITT Population | G-GT high >3*ULN in U/L | 1 participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population
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.
Time frame: Day 1 to Week12
Population: ITT population included all participants treated with at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Withdrawal due to AE | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Death | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | SAE | 0 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | TEAE | 26 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Injection Site TEAEs | 16 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | SAE | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | TEAE | 22 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Death | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Withdrawal due to AE | 0 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Injection Site TEAEs | 18 participants |
| Cohort 2 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | TEAE | 9 participants |
| Cohort 2 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Withdrawal due to AE | 0 participants |
| Cohort 2 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Injection Site TEAEs | 7 participants |
| Cohort 2 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | SAE | 1 participants |
| Cohort 2 Placebo | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Injection Site TEAEs, Serious Adverse Events (SAEs), Deaths, and Withdrawals Due to AEs in Cohort 1 and Cohort 2 in Intent to Treat (ITT) Population | Death | 0 participants |
Primary
Time to Maximum Concentration (Tmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population
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.
Time frame: Day 1, Week 12
Population: PK evaluable population. n=number of participants who had reliable PK data available to be evaluated.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Time to Maximum Concentration (Tmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Tmax (0 to 8 hours), n=27 | 7.0 hours | Standard Error 0.43 |
| Cohort 1 Exenatide 10 mg | Time to Maximum Concentration (Tmax) for Single Dose of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | Tmax (0 hour to Week 12), n=30 | 998.1 hours | Standard Error 67.6 |
Primary
Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population
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.
Time frame: Week 10, Weeks 10-11, Weeks 10-12
Population: PK evaluable population was analyzed. In categories below, n = number of ITT participants with PK evaluable data. Note: Placebo-treated participants not included in this analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population | Tmax 0-6 h Week; n=18 | 1.4 hours | Standard Error 0.2 |
| Cohort 1 Exenatide 10 mg | Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population | Tmax 0-168 h Weeks 10-11; n=18 | 34.3 hours | Standard Error 13.96 |
| Cohort 1 Exenatide 10 mg | Time to Maximum Concentration (Tmax) of 2 mg Exenatide (Cohort 2) in Participants With Diabetes in Pharmacokinetic Evaluable Population | Tmax 0-tlast Weeks 10-12; n=17 | 60.0 hours | Standard Error 26.01 |
Secondary
AUC (0 Hour to 168 Hour) for 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population
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. At all visits following the single injection, a single blood sample was collected for assessment of exenatide concentrations. AUC (0-168 h) data represents average concentration rather than maximum concentration. Exenatide concentration was measured using a validated enzyme-linked immunosorbent assay (ELISA). AUC calculated using linear trapezoidal method from time x to time y and measured in pg\*h/mL. 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.
Time frame: Day 1 to Week 1
Population: PK evaluable population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | AUC (0 Hour to 168 Hour) for 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | 3269.6 pg*h/mL | Standard Error 1661.45 |
Secondary
Average Exenatide Concentration (Cave) of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population
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. At all visits following the single dose, a single blood sample was collected for assessment of exenatide concentrations. Cave(0-168h) was the time-weighted mean concentration over the sampling period from time x to time y corresponding to AUC (0-168h) and 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 and had reliable PK data.
Time frame: Day 1 to Week 1
Population: PK evaluable population.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Average Exenatide Concentration (Cave) of 10 mg Exenatide (Cohort 1) in Healthy Participants in the Pharmacokinetic Evaluable Population | 32.5 pg/mL | Standard Error 7.53 |
Secondary
Least Square Mean Change From Baseline in Hemoglobin A1c (HbA1c) to Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population
HbA1c was measured as a percent of hemoglobin at screening, Day 1, Weeks 4, 8, 12 or early termination. Last observation carried forward (LOCF) was applied to estimate missing values at post baseline timepoints. Baseline=Day 1, last measurement prior to first dose of study drug.
Time frame: Day 1 to Week 12
Population: ITT population included all participants treated with at least one dose of study drug. This analysis was only done in Cohort 2 so the ITT population of Cohort 2 was available for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Least Square Mean Change From Baseline in Hemoglobin A1c (HbA1c) to Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | -0.87 Percent of hemoglobin | Standard Error 0.179 |
| Cohort 2 Exenatide 2 mg | Least Square Mean Change From Baseline in Hemoglobin A1c (HbA1c) to Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | 0.08 Percent of hemoglobin | Standard Error 0.231 |
p-value: 0.001395% CI: [-1.5, -0.4]ANOVA
Secondary
Mean Change From Baseline at Week 12 in Body Weight in Participants With Diabetes (Cohort 2) in the ITT Population
Body weight was measured in kilograms (kg). Baseline was Day 1, last measurement prior to first dose of study drug. Body weight was measured at screening, Day 1, Weeks 4, 8, 12 or early termination and the LOCF approach was applied to estimate missing value at each post baseline timepoint.
Time frame: Baseline, Week 12
Population: ITT population included all participants treated with at least one dose of study drug. Only Cohort 2 was analyzed for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Mean Change From Baseline at Week 12 in Body Weight in Participants With Diabetes (Cohort 2) in the ITT Population | -1.41 kg | Standard Error 0.558 |
| Cohort 2 Exenatide 2 mg | Mean Change From Baseline at Week 12 in Body Weight in Participants With Diabetes (Cohort 2) in the ITT Population | -0.39 kg | Standard Error 0.717 |
Comparison: Least square mean (LS) mean, 95% confidence interval (CI) and p-value calculated for the changes in weight from baseline in participants in cohort 2 treated with exenatide with placebo as reference group.p-value: 0.228595% CI: [-2.73, 0.68]ANOVA
Secondary
Mean Change From Baseline at Week 12 in Fasting Plasma Glucose in Participants With Diabetes (Cohort 2) for the ITT Population
Baseline was the last measurement at the screening visit. Fasting plasma glucose (FPG) was measured at screening, Day 1, Weeks 2, 4, 6, 8, 12, or early termination and reported in milligrams per deciliter (mg/dL).
Time frame: Baseline, Week 12
Population: ITT population included all participants treated with at least one dose of study drug. Only participants in Cohort 2 were evaluated for this Outcome Measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Mean Change From Baseline at Week 12 in Fasting Plasma Glucose in Participants With Diabetes (Cohort 2) for the ITT Population | -32 mg/dL | Standard Error 9.9 |
| Cohort 2 Exenatide 2 mg | Mean Change From Baseline at Week 12 in Fasting Plasma Glucose in Participants With Diabetes (Cohort 2) for the ITT Population | 8 mg/dL | Standard Error 11.9 |
p-value: 0.003595% CI: [-66.5, -14.3]ANOVA
Secondary
Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population
HbA1c was measured as a percent of hemoglobin at screening, Day 1, Weeks 4, 8, 12 or early termination. LOCF was applied to estimate missing values at post baseline timepoints. Baseline=Day 1, last measurement prior to first dose of study drug.
Time frame: Week 12
Population: ITT population included all participants treated with at least one dose of study drug. Only those ITT participants in Cohort 2 were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 Exenatide 10 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Baseline HbA1c >= 7% | 22 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Week 12 HbA1c <= 6.5% | 9 participants |
| Cohort 1 Exenatide 10 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Week 12 HbA1c <7% | 14 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Baseline HbA1c >= 7% | 12 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Week 12 HbA1c <= 6.5% | 1 participants |
| Cohort 2 Exenatide 2 mg | Number of Participants Achieving HbA1c Less Than Equal to (<=) 6.5% and Less Than (<) 7% at Week 12 in Participants With Diabetes (Cohort 2) in the ITT Population | Week 12 HbA1c <7% | 2 participants |
p-value: 0.0033Cochran-Mantel-Haenszel