A Study Assessing Saxagliptin Treatment in Type 2 Diabetic Subjects Who Are Not Controlled With TZD Therapy Alone

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical research study is to learn whether Saxagliptin added to thiazolidinedione (TZD) therapy is more effective than TZD alone as a treatment for Type 2 diabetic subjects who are not sufficiently controlled with TZD alone

Detailed Description
-----------------
All subjects will participate in a lead-in period, and qualifying subjects will continue into a short-term randomized treatment period. Subjects who complete the short-term period will be eligible to enter the long term extension period. Also, subjects in the short-term period who have an elevated blood sugar that requires additional medication for blood sugar control will be eligible to enter the long-term treatment extension period where they will receive metformin (defined as rescue medication) added onto their blinded study medication

Official Title
-----------------
A Multicenter, Randomized, Double Blind, Placebo Controlled, Phase III Trial to Evaluate the Efficacy and Safety of Saxagliptin (BMS477118) in Combination With Thiazolidinedione Therapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Thiazolidinedione Therapy Alone

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

Intervention / Treatment
-----------------
* Drug: Saxagliptin
* Drug: Saxagliptin
* Drug: Placebo
* Drug: pioglitazone
* Drug: rosiglitazone
* Drug: metformin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetics currently receiving a stable dose of TZD monotherapy (pioglitazone 30mg or 45mg, or rosiglitazone 4mg or 8mg) for at least 12 weeks prior to screening. Hemoglobin A1c (HbA1c) > = 7.0% and < = 10.5% Body mass index < = 45kg/m2 Fasting C-peptide > = 1 ng/mL Exclusion Criteria: Symptomatic poorly controlled diabetes Recent cardiac or cerebrovascular event Serum creatinine > = 2.0 mg/dL

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 77 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saxagliptin plus open-label TZD (A)<br>Saxagliptin PLUS pioglitazone OR rosiglitazone PLUS open-label metformin (as needed as rescue medication) | Drug: Saxagliptin<br>* Tablets, Oral, 2.5 mg, Once daily (6 months ST, 12 months LT)<br>* Other names: BMS-477118;Drug: pioglitazone<br>* Tablets, Oral, 30 mg or 45 mg, once daily (6 months ST, 12 months LT)<br>Drug: rosiglitazone<br>* Tablets, Oral, 4 mg, once daily or 8 mg, either as once or twice daily (6 months ST, 12 months LT)<br>Drug: metformin<br>* Tablets, Oral, 500-2500 mg, as needed (12 months LT)<br>|
| Experimental: Saxagliptin plus open-label TZD (B)<br>Saxagliptin PLUS pioglitazone OR rosiglitazone PLUS open-label metformin (as needed as rescue medication) | Drug: Saxagliptin<br>* Tablets, Oral, 5 mg, once daily (6 months ST, 12 months LT)<br>* Other names: BMS-477118;Drug: pioglitazone<br>* Tablets, Oral, 30 mg or 45 mg, once daily (6 months ST, 12 months LT)<br>Drug: rosiglitazone<br>* Tablets, Oral, 4 mg, once daily or 8 mg, either as once or twice daily (6 months ST, 12 months LT)<br>Drug: metformin<br>* Tablets, Oral, 500-2500 mg, as needed (12 months LT)<br>|
| Placebo Comparator: Placebo plus open-label TZD (C)<br>Placebo PLUS pioglitazone OR rosiglitazone PLUS open-label metformin (as needed as rescue medication) | Drug: Placebo<br>* Tablets, Oral, 0 mg, Once daily (6 months ST, 12 months LT)<br>Drug: pioglitazone<br>* Tablets, Oral, 30 mg or 45 mg, once daily (6 months ST, 12 months LT)<br>Drug: rosiglitazone<br>* Tablets, Oral, 4 mg, once daily or 8 mg, either as once or twice daily (6 months ST, 12 months LT)<br>Drug: metformin<br>* Tablets, Oral, 500-2500 mg, as needed (12 months LT)<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (A1C) at Week 24 | Mean change from baseline in A1C at Week 24, adjusted for baseline value. | Baseline, Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | Mean change from baseline in FPG at Week 24, adjusted for baseline value. | Baseline, Week 24 | 
| Percentage of Participants Achieving A1c <7% at Week 24 | Percentage of participants achieving A1C < 7%, the American Diabetic Association's defined goal for glycemia, at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24. | Week 24 | 
| Changes From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Oral Glucose Tolerance Test (OGTT) at Week 24 | Mean change from baseline for 0 to 180 minutes PPG AUC achieved at each dose of saxagliptin plus TZD versus placebo plus TZD at Week 24, adjusted for baseline value. | Baseline, Week 24 |