Evaluate the Efficacy and Safety of Saxagliptin in Combination With Metformin IR Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Drug Naive Chinese Subjects With Type 2 Diabetes Who Have Inadequate Glycaemic Control

Study Overview
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Brief Summary
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A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin in Combination with Metformin IR as Initial Therapy Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Subjects with Type 2 Diabetes who have Inadequate Glycaemic Control

Detailed Description
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Allocation: Randomized Endpoint Classification: Efficacy/Safety study Intervention Model: Parallel Assignment Masking: Double Blind Primary Purpose: Treatment

Official Title
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A Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Trial to Evaluate the Efficacy and Safety of Saxagliptin in Combination With Metformin IR as Initial Therapy Compared to Saxagliptin Monotherapy and to Metformin IR Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycaemic Control

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Saxagliptin 5 mg
* Drug: Placebo 5 mg for Saxagliptin
* Drug: Placebo 500 mg for metformin (with titration)
* Drug: Metformin 500 mg with titration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Subjects with type 2 diabetes mellitus; 2. HbA1c ≥8% but ≤12%; 3.Fasting C-peptide ≥1.0 ng/ml; 4. Subject will be drug naïve; 5. Body mass index ≤40 kg/m2. Exclusion Criteria: 1. Symptoms of poorly controlled diabetes; 2. Chronic or repeated intermittent corticosteroid treatment ; 3. Calculated creatinine clearance <60 ml/min or serum creatinine >132.6 μmol/L (>1.5 mg/dL) for men, >123.8 μmol/L (>1.4 mg/dL) for women; 4. Creatine Kinase ≥3x ULN; 5.Abnormal TSH value at screening will be further evaluated by free T4, subjects with an abnormal free T4 will be excluded; 6. History of administration of any antihyperglycaemic therapy for a total of 28 days or for more than three consecutive days or a total of seven non-consecutive days during the eight weeks prior to screening; 7. Current treatment with a strong CYP3A4/5 inhibitor; 8. Prior treatment with saxagliptin or any DPP-4 inhibitor; 9. Significant or history of cardiovascular disease, renal disease, psychiatric disorders, Immunocompromised individuals, hemoglobinopathies, liver disease, Pancreatitis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Saxagliptin 5 mg + Metformin (500 mg with titration)<br>Saxagliptin 5 mg once daily and metformin 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. | Drug: Saxagliptin 5 mg<br>* Tablet, Oral, 5 mg, Once daily in the morning<br>* Other names: BMS-477118;Drug: Metformin 500 mg with titration<br>* Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration.<br>* Other names: Glucophage;|
| Active Comparator: Saxagliptin 5 mg + Placebo<br>Saxagliptin 5 mg once daily and Placebo 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. | Drug: Saxagliptin 5 mg<br>* Tablet, Oral, 5 mg, Once daily in the morning<br>* Other names: BMS-477118;Drug: Placebo 500 mg for metformin (with titration)<br>* Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration.<br>|
| Active Comparator: Metformin (500 mg with titration) + Placebo<br>Placebo 5 mg once daily and metformin 500 mg once daily, then titrate. Acarbose will be used as rescue medication as needed. | Drug: Placebo 5 mg for Saxagliptin<br>* Tablet, Oral, 5 mg, Once daily in the morning<br>Drug: Metformin 500 mg with titration<br>* Tablet, 500 mg, Once daily in the evening the first two weeks and thereafter according to titration.<br>* Other names: Glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HbA1c From Baseline to Week 24 Provided That it is Prior to Rescue | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in HbA1c (%) at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 (prior to rescue) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glycemic Response Defined as HbA1c < 7.0% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c < 7.0% at the end of 24 weeks of double-blinded treatment. | Week 24 (prior to rescue) | 
| Change From Baseline to Week 24 (Prior to Rescue) in Fasting Plasma Glucose | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to reduction in fasting plasma glucose at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue | 
| Change From Baseline to Week 24 (Prior to Rescue) in Area Under the Curve From 0-180 Minutes for Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 180-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue | 
| Glycemic Response Defined as HbA1c ≤ 6.5% at Week 24 | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects achieving a therapeutic glycemic response defined as HbA1c ≤ 6.5% at the end of 24 weeks of double-blinded treatment. | Week 24 (prior to rescue) | 
| Change From Baseline to Week 24 in 120-minute Postprandial Glucose Response to a Meal Tolerance Test | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to change in 120-minute postprandial glucose response to a meal tolerance test at the end of 24 weeks of double-blinded treatment. | Baseline to Week 24 prior to rescue | 
| Patients Rescued for Failing to Achieve Pre-specified Glycemic Targets or Discontinuation for Lack of Efficacy During the 24-week Double-blind Treatment Phase | To evaluate the efficacy of the combination therapy (saxagliptin + metformin) when compared to placebo + metformin and placebo + saxagliptin with respect to the proportion of subjects requiring rescue for failing to achieve pre-specified glycemic targets or discontinuing for lack of efficacy within the 24 weeks of double-blinded treatment. | Baseline to Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes Mellitus, Dipeptidyl-Peptidase 4 Inhibitors, Saxagliptin, Metformin, Endocrine System Diseases