Safety and Efficacy of Dapagliflozin in Asian T2DM Subjects With Inadequate Glycemic Control on Metformin/Saxagliptin

Study Overview
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Brief Summary
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This is a 24-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel group, phase 3 study designed to evaluate if the safety and efficacy of dapagliflozin 5 mg or 10 mg added to saxagliptin 5 mg plus metformin is superior to placebo added to saxagliptin 5 mg plus metformin in reducing hemoglobin A1c (HbA1c).

Detailed Description
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This study will be conducted in approximately 36 sites in Asian countries. Approximately 1004 subjects will be screened and 342 randomized. Prior to the screening, subjects of Stratum A should have a stable dose of metformin (≥1500 mg/day or a maximal tolerated dose) for at least 8 weeks. And subjects of Stratum B should have a stable dose of metformin (≥1500 mg/day or a maximal tolerated dose) AND a dipeptidyl peptidase-4 inhibitor at maximum approved dose for at least 8 weeks prior to the screening. Eligible subjects who complete the screening visit will enter the lead-in period, which includes open-label saxagliptin 5 mg and metformin treatment for 16 weeks in Stratum A or 8 weeks in Stratum B. At randomization visit, eligible subjects will be randomized into 1 of 3 treatment groups in a 1:1:1 ratio, receiving blinded dapagliflozin 5 mg, 10 mg or placebo plus metformin and saxagliptin 5 mg treatment for 24 weeks.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Asian Subjects With T2DM and Inadequate Glycemic Control on Metformin and Saxagliptin (DS Navigation)

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin 10 mg
* Drug: Dapagliflozin 5 mg
* Drug: Dapagliflozin 10 mg placebo to match
* Drug: Dapagliflozin 5 mg placebo to match
* Drug: Saxagliptin 5 mg
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent before participating in the study Diagnosed with type 2 diabetes mellitus Inadequate glycemic control defined as below: HbA1c ≥ 8.0% and ≤ 11.5% for Stratum A and HbA1c ≥ 7.5% and ≤ 10.5% for Stratum B at screening visit HbA1c ≥ 7.0 and ≤ 10.5% for both strata at Week -2 visit Body mass index ≤ 40.0 kg/m^2 Exclusion Criteria: Women of childbearing potential unable or unwilling to use acceptable birth control, or women who are pregnant or breastfeeding History of diabetes insipidus and type 1 diabetes History of diabetic ketoacidosis requiring medical intervention within 1 month prior to screening Subjects with moderate to severe renal impairment (defined as estimate glomerular filtration rate calculated by the MDRD Formula < 60mL/min/1.73 m^2 or serum creatinine ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females) or end-stage renal disease History of unstable or rapidly progressing renal disease Subjects with significant hepatic disease or severe hepatic impairment, or positive serologic evidence of current infectious liver disease Prohibited Treatment and Therapies Administration of any anti-hyperglycemic therapy [other than metformin, or Dipeptidyl peptidase-4 (DPP-4) inhibitors] for more than 14 days (consecutive or not) during the 8 weeks prior to screening Any use of Sodium glucose cotransporter 2 (SGLT2) inhibitor within 8 weeks prior to screening Prescription and over-the-counter weight loss medications within 3 months prior to screening Current treatment with potent cytochrome P450 3A4/5 inhibitors Malignancy within 5 years of the screening History of hemoglobinopathy Hematuria (by microscopy) positive at screening visit FPG > 270 mg/dL obtained at open-label period An abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: Dapagliflozin 10 mg<br>Dapagliflozin 10 mg and dapagliflozin 5 mg placebo to match added to saxagliptin 5 mg and metformin | Drug: Dapagliflozin 10 mg<br>* 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Dapagliflozin 5 mg placebo to match<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Saxagliptin 5 mg<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B<br>Drug: Metformin<br>* Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period<br>|
| Experimental: Dapagliflozin 5 mg<br>Dapagliflozin 5 mg and dapagliflozin 10 mg placebo to match added to saxagliptin 5 mg and metformin | Drug: Dapagliflozin 5 mg<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Dapagliflozin 10 mg placebo to match<br>* 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Saxagliptin 5 mg<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B<br>Drug: Metformin<br>* Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period<br>|
| Placebo Comparator: Placebo<br>Dapagliflozin 5 mg placebo to match and dapagliflozin 10 mg placebo to match added to saxagliptin 5 mg and metformin | Drug: Dapagliflozin 10 mg placebo to match<br>* 10 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Dapagliflozin 5 mg placebo to match<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blind treatment period<br>Drug: Saxagliptin 5 mg<br>* 5 mg, oral tablet, once daily for 24 weeks of double-blinded treatment period, and for 16 weeks of open-label treatment period in Stratum A or 8 weeks of open-label treatment period in Stratum B<br>Drug: Metformin<br>* Stable dose of metformin immediate release/extended release (≥ 1500 mg/day or at a maximal tolerated dose) throughout the whole study period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in HbA1c at Week 24 | To compare the mean change from baseline in HbA1c achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment | Baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change from baseline in fasting plasma glucose (FPG) at Week 24 | To compare the mean change from baseline in FPG achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment | Baseline to Week 24 | 
| Mean change in 2-hour postprandial glucose during a meal tolerance test (2-hour MTT) at Week 24 | To compare the mean change from baseline in 2-hour postprandial glucose from a meal tolerance test (2-hour MTT) achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment | Baseline to Week 24 | 
| Mean change from baseline in total body weight at Week 24 | To compare the mean change from baseline in total body weight achieved with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin versus placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment | Baseline to Week 24 | 
| Percent of subjects achieving a therapeutic glycaemic response of HbA1c <7.0% at Week 24 | To compare the proportion of subjects achieving a therapeutic glycaemic response of HbA1c < 7.0% with dapagliflozin 5 mg or dapagliflozin 10 mg added to saxagliptin 5 mg plus metformin vs. placebo added to saxagliptin 5 mg plus metformin after 24 weeks of oral administration of double-blind treatment | At week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DPP-4 inhibitor, HbA1c, Incretin, Dapagliflozin