Safety and Efficacy of Saxagliptin Plus Insulin With or Without Metformin

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to compare the effects of saxagliptin with those of placebo as add-on therapy to insulin and insulin with metformin in improving glycemic control at 24 and 52 weeks.

Official Title
-----------------
A Multicenter, Randomized, Double-Blind, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin Added to Insulin Monotherapy or to Insulin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Insulin Alone or on Insulin in Combination With Metformin

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

Intervention / Treatment
-----------------
* Drug: Saxagliptin, 5 mg + insulin
* Drug: Placebo + insulin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 2 diabetes mellitus Must have been taking a stable dose of basal or premixed insulin for 8 weeks or longer prior to screening If taking metformin, must have been taking the same daily dose for 8 weeks or longer prior to screening Insulin type should be intermediate- or long-acting (basal) or premixed (premixed formulation may include short- or rapid-acting insulin as 1 component). Inadequate glycemic control (A1C of 7.5% to 11.0%, inclusive) Body mass index of 45 kg/m² or lower Fasting C-peptide level of 0.8 ng/mL or higher Exclusion Criteria: Symptoms of poorly controlled diabetes, including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the last 3 months prior to screening or other signs and symptoms History of diabetic ketoacidosis or hyperosmolar nonketotic coma Women of childbearing potential unable or unwilling to use acceptable birth control Women who are pregnant or breastfeeding Active liver disease Anemia Chronic or repeated intermittent corticosteroid treatment (participants receiving stable doses of replacement corticosteroid (except dexamethasone) therapy may be enrolled) Use of short- or rapid-acting insulin Significant cardiovascular history defined as: myocardial infarction, coronary angioplasty or bypass graft, valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accident Congestive heart failure Unstable or rapidly progressing renal disease History of alcohol or drug abuse within the previous year History of hemoglobinopathies Unstable major psychiatric disorders Immunocompromised status

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 78 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, 5 mg + insulin<br>Saxagliptin, 5 mg, plus insulin, administered to participants with Type 2 diabetes inadequately controlled with insulin alone or with insulin plus metformin | Drug: Saxagliptin, 5 mg + insulin<br>* Saxagliptin, 5-mg tablets (plus stable insulin dose), given orally once daily (24 weeks short-term, 28 weeks long-term); participants stratified by use of stable metformin dose; flexible insulin dose (as needed for rescue)<br>* Other names: BMS-477118;|
| Placebo Comparator: Placebo + insulin<br>Placebo administered to participants with Type 2 diabetes inadequately controlled with insulin alone or with insulin plus metformin | Drug: Placebo + insulin<br>* Placebo tablets given orally once daily for 24 weeks (short-term period)+ insulin with metformin<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in A1C Levels (Last Observation Carried Forward [LOCF]) | Change from baseline: post-pre. Adjusted for baseline (value and metformin use). ANCOVA model: difference between week t and baseline values=baseline values + treatment + metformin use | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Postprandial Glucose (PPG) Area Under the Curve (AUC) Response to an Meal Tolerance Test (MTT) | An MTT is a 2-part test that measures glucose and insulin levels after an overnight fast and before ingesting a meal consisting of a nutritional drink and power bar and again at prespecified times (30, 60, 120, and 180 minutes) after the start of ingestion of the meal | Baseline to Week 24 | 
| Change From Baseline in 120-minute PPG Values During an MTT | An MTT is a 2-part test that measures glucose and insulin levels after an overnight fast and before ingesting a meal consisting of a nutritional drink and power bar and again at prespecified times (30, 60, 120, and 180 minutes) after the start of ingestion of the meal. | Baseline to Week 24 | 
| Change From Baseline in Fasting Plasma Glucose Values |  | Baseline to Week 24 | 
| Percentage of Participants Achieving a Therapeutic Glycemic Response | Therapeutic glycemic response is defined as an A1C<7%. Significance was not interpreted with a p value. | Baseline to Week 24 | 
| Change From Baseline in Mean Total Daily Dose of Insulin (MTDDI) (LOCF) | Based on information recorded in the participant's daily diary. The MTDDI was calculated at every visit using the values patients recorded since the last regularly scheduled visit (minimum of 80% of days with a value). At every visit, the MTDDI was compared with the participant's baseline MTDDI (measured during a 4-week lead-in period) to identify any changes in insulin use at that visit compared with insulin use at baseline. | Baseline to Week 24 |