Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus(DURATION - 1)

Study Overview
=================
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.

Official Title
-----------------
A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release on Glucose Control (HbA1c) and Safety in Subjects With Type 2 Diabetes Mellitus Managed With Diet Modification and Exercise and/or Oral Antidiabetic Medications

Conditions
-----------------
Type 2 Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: exenatide, long acting release
* Drug: exenatide


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide Once Weekly<br>Subcutaneous injection (SC), once a week of long acting release (LAR) exenatide. | Drug: exenatide, long acting release<br> <br> * Other names: BYDUREON;|
| Active Comparator: Exenatide Twice Daily<br>subcutaneous injection (SC), twice a day for the first 30 weeks, followed by exenatide LAR SC injection weekly for the remainder of the study. Sub-study: Exenatide 2 mg subcutaneous injection, Administered Using the Exenatide Once Weekly Single-Dose Tray , once a week for 11 visits, switch to Exenatide 2 mg subcutaneous injection, Administered Using the Dual chamber pen device. Exenatide 2mg SC injection administered using the Dual chamber pen device. | Drug: exenatide<br> <br> * Other names: Byetta;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 30 | Absolute change in HbA1c from Baseline (Day -3) to Week 30 [Week 30 - Baseline] | Day -3, Week 30 | 
| 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 | Week 22 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c From Baseline to Week 364 | Absolute change in HbA1c from Baseline (Day -3) to Week 364 | Day -3, Week 364 | 
| Percentage of Subjects Achieving HbA1c Target of <7% | Percentage of subjects achieving HbA1c target value of <7% at Week 30. | Week 30 | 
| Percentage of Subjects Achieving HbA1c Target of <7% | Percentages of subjects achieving HbA1c target value of <7% at Week 364 | Week 364 | 
| Percentage of Subjects Achieving HbA1c Target of <=6.5% | Percentages of subjects achieving HbA1c target values of <=6.5% at Week 30. | Week 30 | 
| Percentage of Subjects Achieving HbA1c Target of <=6.5% | Percentages of subjects achieving HbA1c target values of <=6.5% at Week 364 | Week 364 | 
| Percentage of Subjects Achieving HbA1c Target of <=6.0% | Percentage of subjects achieving HbA1c target values of <=6.0% at Week 30. | Week 30 | 
| 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. | Week 29 to Week 30 | 
| Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14 | Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14 | Day -3, 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) | 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. | Week 22 | 
| Change in Body Weight From Baseline to Week 30 | Change in body weight from baseline (Day -3) to Week 30 | Day -3, Week 30 | 
| Change in Body Weight From Baseline to Week 364 | Change in body weight from baseline (Day -3) to Week 364 | Day -3, Week 364 | 
| Change in Fasting Plasma Glucose From Baseline to Week 30 | Change in fasting plasma glucose from baseline (Day -3) to Week 30. | Day -3, Week 30 | 
| Change in Fasting Plasma Glucose From Baseline to Week 364 | Change in fasting plasma glucose from baseline (Day -3) to Week 364. | Day -3, Week 364 | 
| 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 | Day -3, Week 30 | 
| 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 | Day -3, Week 364 | 
| Change in Total Cholesterol From Baseline to Week 30 | Change in total cholesterol from baseline (Day -3) to Week 30. | Day -3, Week 30 | 
| Change in Total Cholesterol From Baseline to Week 364 | Change in total cholesterol from baseline (Day -3) to Week 364. | Day -3, Week 364 | 
| 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. | Day -3, Week 30 | 
| 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. | Day -3, Week 364 | 
| 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. | Day -3, Week 364 | 
| 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. | Day -3, Week 30 | 
| 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. | Day -3, Week 364 | 
| 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. | Day 1 to Week 364 | 
| 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. | Day 1 to Week 364 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
LAR, diabetes, exenatide, long acting release, Amylin, Lilly