A 52-week International, Multicenter Trial With a Long -Term Extension to Evaluate Saxagliptin With Dapagliflozin in Combination With Metformin Compared to Glimepiride in Combination With Metformin in Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone

Study Overview
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Brief Summary
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This clincial trial is evaluating if the co-administration of saxagliptin and dapagliflozin, in addition to metformin, results in better glycemic control, as measured by HbA1c, over a treatment period of 52 weeks, compared to the addition of glimepiride to metformin in subjects with Type 2 Diabetes Mellitus who have inadequate glycemic control on Metformin Alone. We will compare the change from baseline in HbA1c achieved with saxagliptin, in co-administration with dapagliflozin, added to current background therapy with metformin compared to glimepiride added to current background therapy with metformin ≥1500 mg at Week 52.

Official Title
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A 52-week International, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel Group, Phase 3bTrial With a Blinded 104-week Long -Term Extension Period to Evaluate the Efficacy and Safety of Saxagliptin Co-administered With Dapagliflozin in Combination With Metformin Compared to Glimepiride in Combination With Metformin ≥1500 mg in Adult Patients With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Therapy Alone

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Saxagliptin
* Drug: Dapagliflozin
* Drug: Glimepiride
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: Subjects must be willing and able to give signed and dated written informed consent Patients with Type 2 diabetes mellitus (T2DM) with inadequate glycemic control Subjects should have been taking the same daily dose of metformin ≥ 1500 mg Fasting Plasma Glucose ≤ 270 mg/dL (≤15 mmol/L) Males and females, aged ≥18 years old at time of screening visit Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test WOCBP and males must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug Exclusion Criteria: Clinical diagnosis of type I diabetes History of diabetic ketoacidosis Cardiovascular/vascular diseases within 3 months of the enrollment Renal disease Hepatic diseases History of, or currently, acute or chronic pancreatitis Hematological and oncological disease/conditions Patients who have contraindications to therapy being studied Patients on weight loss program(s) Replacement or chronic systemic corticosteroid therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saxagliptin 5 mg/ dapagliflozin 10mg or Placebo<br>Saxagliptin 5 mg /dapagliflozin 10 mg Placebo once a day orally | Drug: Saxagliptin<br> <br> Drug: Dapagliflozin<br> <br> Other: Placebo<br> <br> |
| Experimental: Glimepiride or Placebo<br>Glimepiride or placebo 1mg or 2mg or 3mg or 4mg or 6mg once a day orally | Drug: Glimepiride<br> <br> Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Hemoglobin A1c (HbA1c) at Week 52 | To examine whether the mean change from baseline in HbA1c with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Body Weight at Week 52 | To examine whether the mean change from baseline in total body weight with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. | Baseline and Week 52 | 
| Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 52 | Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 52 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c. | At Week 52 | 
| Change From Baseline in Systolic Blood Pressure (SBP) at Week 52 | To examine whether the change from baseline in SBP with co-administered saxagliptin 5 mg and dapagliflozin 10 mg plus metformin is superior to titrated glimepiride plus metformin after 52 weeks of double-blind treatment. | Baseline and Week 52 | 
| Percentage of Subjects With Treatment Intensification During the 52-week Short-term Treatment Period | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after the 52-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 52 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 52-week short -term treatment period. | Up to Week 52 | 
| Percentage of Subjects With Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. The values presented are the percentage of subjects requiring the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control during the 156-week treatment period. | Up to Week 156 | 
| Percentage of Subjects Achieving a Therapeutic Glycemic Response, Defined as HbA1c < 7.0%, at Week 156 | Therapeutic glycemic response was defined as HbA1c <7.0%. Subjects rescued or discontinued prior to, and subjects with missing measurements at Week 156 were treated as non-responders. The percentage of subjects with a therapeutic glycemic response is based on the logistic regression method with adjustment for baseline HbA1c. | At Week 156 | 
| Time to Treatment Intensification During the 156-Week Short-term Plus Long-Term Treatment Period. | Treatment intensification was defined as the addition of insulin or other glucose-lowering agent for rescue therapy or discontinuation for lack of glycemic control. Time to treatment intensification was censored after 156-week treatment period if treatment intensification had not occurred by then. Subjects rescued at Week 156 were counted as having an event for the analysis. Time to treatment intensification curves were generated using Kaplan-Meier estimates and compared using a Cox proportional hazards model. | Up to Week 156 |