A Pilot Study of BMS-512148 in Subjects With Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical research study is to learn if BMS-512148, added to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone), can help reduce the blood sugar levels compared to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone) alone, in subjects with type 2 diabetes. The safety of this treatment will also be studied.

Official Title
-----------------
A Pilot Study of the Efficacy and Safety of BMS-512148 on Glycemic Control in Subjects With Type 2 Diabetes Treated Aggressively But Not Controlled on Combination Antihyperglycemic Therapy With Metformin and/or Thiazolidinedione (TZD) and Insulin.

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

Intervention / Treatment
-----------------
* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, 18 to 75 years old, with type 2 diabetes with inadequate glycemic control Subjects receiving insulin and metformin and/or a thiazolidinedione Body Mass Index <=45.0 kg/m2 Serum creatinine <1.5 mg/dL for men or <1.4 mg/dL for women No overt proteinuria (in subjects with a microalbumin/creatinine ratio ≥300 mg/g, the 24-hour urinary excretion of total protein must be <3 g/24 hrs) Exclusion Criteria: History of type 1 diabetes AST and/or ALT >2.5 times the upper limit of normal Creatinine kinase ≥3 times the upper limit of normal Symptoms of severely uncontrolled diabetes History of hypoglycemic unawareness Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 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: Cohort 1<br>20 mg | Drug: Dapagliflozin<br>* Tablets, Oral, once daily, up to 12 weeks<br>* Other names: BMS-512148;|
| Experimental: Cohort 2 - Arm 1<br>10 mg | Drug: Dapagliflozin<br>* Tablets, Oral, once daily, up to 12 weeks<br>* Other names: BMS-512148;|
| Experimental: Cohort 2 - Arm 2<br>20 mg | Drug: Dapagliflozin<br>* Tablets, Oral, once daily, up to 12 weeks<br>* Other names: BMS-512148;|
| Placebo Comparator: Cohort 2 - Arm 3<br> | Drug: Placebo<br>* Tablets, Oral, 0 mg, once daily, up to 12 weeks<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | HbA1c was measured as percent of hemoglobin by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 6, 8, 10, and 12 in the double-blind period. | From Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Data after insulin uptitration was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 6, 8, 10, and 12 in the double-blind period. | From Baseline to Week 12 | 
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | Therapeutic glycemic response is defined as HbA1c <7.0%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. | From Baseline to Week 12 | 
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <=6.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | Therapeutic glycemic response is defined as HbA1c <=6.5%. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. | From Baseline to Week 12 | 
| Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) Decrease From Baseline >= 0.5% at Week 12 (Last Observation Carried Forward [LOCF]) - Cohort 2 | Therapeutic glycemic response is defined as HbA1c decrease from baseline >= 0.5% at Week 12. Data after insulin uptitration was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. | From Baseline to Week 12 | 
| Adjusted Mean Total Daily Dose of Insulin (TDDI) Change From Baseline at Week 12 (LOCF), Including Data After Up-titration of Insulin) - Cohort 2 | Baseline TDDI was reduced by 50% prior to treatment, except 2 subjects. TDDI could be up-titrated according to prespecified criteria at Weeks 4, 6, 8, 10 and 12 in the double-blind period. | From Baseline to Week 12 |