An Evaluation of Exenatide and Rosiglitazone in Subjects With Type 2 Diabetes Mellitus

• Change in AUC for Glucose During a Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in AUC(15-180 min) for glucose during a MCT baseline to week 20.
• Change in Insulin Sensitivity Index as Measured by M-value. [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change of M-Value (mg/kg-min) during hyperinsulinemic euglycemic clamp test from baseline to week 20.
• Change in Insulin AUC in the First Stage From Baseline to Endpoint. [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in insulin AUC in the first stage(uIU-min/ml) from baseline to week 20. "First stage" represents the first 10 minutes after reaching a steady state during a hyperglycemic clamp test.
• Change in Insulin iAUC From Baseline to Endpoint. [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in insulin iAUC in the first stage(uIU-min/ml) from baseline to week 20. "First stage" represents the first 10 minutes after reaching a steady state during a hyperglycemic clamp test.
• Ratio (Value at Endpoint Divided by Value at Baseline) of AUC for Insulin During a Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Ratio (value at endpoint divided by value at baseline) of AUC (15-180 min) for insulin (uIU-min/ml) during MCT.
• Change in AUC for C-peptide During a Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Ratio (value at endpoint divided by value at baseline) of AUC(15-180 min) for C-peptide (nmol-min/L) during a MCT from baseline to week 20.
• Change in Incremental for Postprandial Glucose During a Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in incremental for postprandial glucose (mmol/L) during a MCT from baseline to week 20.
• Change in Incremental for Postprandial Insulin During Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in incremental for postprandial insulin (mmol/L) during meal challenge test (MCT) from baseline to week 20.
• Change in Incremental for Postprandial C-peptide During Meal Challenge Test (MCT). [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in incremental for postprandial C-peptide (mmol/L) during MCT from baseline to week 20.
• Change in HbA1c [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in HbA1c from baseline to week 20.
• Change in Fasting Serum Glucose Concentration. [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting serum glucose concentration from baseline to week 20.
• Change in Fasting C-peptide [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting C-peptide from baseline to week 20.
• Change in Fasting Insulin [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting insulin from baseline to week 20.
• Change in Fasting Proinsulin [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Ratio (endpoint value divided by baseline value) for fasting proinsulin, comparing endpoint (week 20) to baseline
• Change in Body Weight [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in body weight from baseline to week 20.
• Change in Fasting Total Cholesterol. [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting total cholestrol from baseline to week 20.
• Change in Fasting HDL Cholesterol [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting high-density lipoprotein (HDL) cholesterol from baseline to week 20.
• Change in Fasting LDL Cholesterol [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Change in fasting low-density lipoprotein (LDL) cholesterol from baseline to week 20.
• Change in Fasting Triglycerides [ Time Frame: Week 20 ] [ Designated as safety issue: No ]
  Ratio (endpint value divided by baseline value) of fasting triglycerides from baseline to week 20.
• Change in Percent Body Fat During a Meal Challenge Test (MCT) [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in percent body fat from baseline to week 20, as assessed during an MCT
• Change in Body Fat Mass During a Meal Challenge Test (MCT) [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in body fat mass form baseline to week 20, as assessed during an MCT
• Change in Lean Body Mass During a Meal Challenge Test (MCT) [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in lean body mass from baseline to week 20, as assessed during an MCT
• Change in Waist Circumference [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in waist circumference from baseline to week 20
• Change in Hip Circumference [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in hip circumference form baseline to week 20
• Change in Waist-to-hip Ratio [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Change in waist-to-hip ratio (waist circumference divided by hip circumference) from baseline to week 20
• Incidence of Hypoglycemia Events [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Number of subjects experiencing hypoglycemia at any point during the study
• Hypoglycemia Rate Per 30 Days Per Patient [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Average number of episodes of hypoglycemia per 30 days per patient
• Pedal Edema Score [ Time Frame: 20 weeks ] [ Designated as safety issue: No ]
  Pedal edema scores experienced by each patient throughout the study ("1+" indicates a patient experienced a pedal edema score of 1 , 2, or 3; "2+" indicates a patient experienced a pedal edema score of 2 or 3, etc.)

• *Compare the effects of exenatide, rosiglitazone, and a combination of exenatide and rosiglitazone in subjects with type 2 diabetes treated with metformin on various pharmacodynamic measurements and safety and tolerability.
• *Compare total insulin secretion between the exenatide group, rosiglitazone group, and the exenatide plus rosiglitazone group.

This protocol is designed to evaluate the metabolic effects of adding exenatide, rosiglitazone, or both to an existing regimen of metformin in subjects with inadequate glycemic control.

• Drug: exenatide
  subcutaneous injection, 5mcg or 10mcg, twice a day
  Other Name: Byetta
• Drug: rosiglitazone
  oral tablet, 2mg or 4mg, twice a day
  Other Name: Avandia

• Experimental: Exenatide Arm
  Intervention: Drug: exenatide
• Experimental: Exenatide plus Rosiglitazone Arm
  Interventions:

  • Drug: exenatide
  • Drug: rosiglitazone
• Experimental: Rosiglitazone Arm
  Intervention: Drug: rosiglitazone

• Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012 Jun;14(6):546-54. doi: 10.1111/j.1463-1326.2012.01561.x. Epub 2012 Feb 10.
• DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010 May;33(5):951-7. Epub 2010 Jan 27.

Inclusion Criteria:

• HbA1c of 6.8% to 10.0%, inclusive.
• Body mass index (BMI) of 25 kg/m^2 to 40 kg/m^2, inclusive.

Exclusion Criteria:

• Have participated in this study previously, or have received exenatide, pramlintide acetate, GLP-1 analogs, or dipeptidyl peptidase-IV (DPP-IV) inhibitors
• Have participated in an interventional, medical, surgical, or pharmaceutical study (a study in which an experimental, drug, medical, or surgical treatment was given) within 30 days of study start. This criterion includes drugs that have not received regulatory approval for any indication at the time of study start.

• Treated with any of the following medications:

  • Thiazolidinedione within 5 months of screening;
  • Sulfonylurea within 3 months of screening;
  • Metformin/sulfonylurea combination therapy within 3 months of screening;
  • Alpha-glucosidase inhibitor within 3 months of screening;
  • Meglitinide within 3 months of screening;
  • Insulin for more than 1 week within the 3 months prior to screening.
  • Symlin (pramlintide acetate) injection or Byetta (exenatide) injection at any time
  • Chronic (more than 2 weeks) or recent (within 4 weeks of study start) use of a drug that directly affects gastrointestinal motility
  • Are receiving chronic (lasting longer than 2 weeks) systemic glucocorticoid therapy (excluding topical and inhaled preparations) or have received such therapy within the 4 weeks immediately preceding study start
  • Regular use of a medication with addictive potential such as an opiate, narcotic, or tranquilizer
  • Systemic antineoplastic agent
  • Systemic transplantation medication
  • Drugs for weight loss, including over-the-counter medications, within the 4 months prior to study start