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

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)

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).

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.

Inclusion Criteria:

1. Provision of informed consent before participating in the study

2. Diagnosed with type 2 diabetes mellitus

3. 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

4. Body mass index ≤ 40.0 kg/m^2

Exclusion Criteria:

1. Women of childbearing potential unable or unwilling to use acceptable birth control, or women who are pregnant or breastfeeding

2. History of diabetes insipidus and type 1 diabetes

3. History of diabetic ketoacidosis requiring medical intervention within 1 month prior to screening

4. 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

5. History of unstable or rapidly progressing renal disease

6. Subjects with significant hepatic disease or severe hepatic impairment, or positive serologic evidence of current infectious liver disease

7. 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

8. Malignancy within 5 years of the screening

9. History of hemoglobinopathy

10. Hematuria (by microscopy) positive at screening visit

11. FPG > 270 mg/dL obtained at open-label period

12. An abnormal TSH value at screening will be further evaluated for free T4. Subjects with abnormal free T4 values will be excluded