Efficacy of FDC Regimen of Dapagliflozin/Metformin Compared to Co-administered Dual Therapy on Glycemic Control, Satisfaction and Adherence in Chinese Patients With T2DM

Study D1690L00149 is a 24-week, multicentre, randomized, parallel, interventional, non-inferiority, open-label study designed to compare the FDC Regimen of Dapagliflozin/Metformin XR with the Dapagliflozin co-administered with Metformin XR in glycemic lowering control, satisfaction and adherence in Chinese patients with T2DM.

The past 30 years have witnessed significant increases in the prevalence of type 2 diabetes mellitus (T2DM) in China. China now is estimated 114 million people with diabetes, T2DM accounts for more than 90% of the overall population with diabetes in China. A large proportion of diabetes is undiagnosed in China: in the 2007-2008 national survey among adult population over 20 years, patient with newly diagnosed diabetes accounted for 60% of total diabetes population. In the Healthy China 2030 Plan, approved by the State Council and the Party's Central Committee, diabetes, along with cancer, hypertension, and cardiovascular diseases, are listed as the four major non-communicable diseases (NCDs) for which the goal is to "control the prevalence and reduce the probability of early death". Metformin hydrochloride is the primary biguanide medication currently used in China's medical practice. Sodium-glucose cotransporter 2 (SGLT2) inhibitors used to be considered as second-line treatment after Metformin in patients with T2DM. But according to the American Diabetes Association (ADA) 2023 Standards of Medical Care in Diabetes, SGLT2 inhibitors are now recommended to be started at the time of diagnosis as the first-line medications, for high-risk individuals with atherosclerotic cardiovascular disease (ASCVD), heart failure (HF) or chronic kidney disease (CKD). Compared with stepwise therapy, early combination therapy may provide earlier and greater reductions in HbA1c and thus achievement of glycemic target. In addition, SGLT2 inhibitors provide cardiorenal protection both in patients with and without T2DM, that goes beyond glycemic control, hence the recommendation by guidelines to implement SGLT2 inhibitors. But early combination therapy is not fully implemented into clinical practice in China. International and CDS guidelines recommends encourage using fixed-dose combination (FDC) to have better adherence, which is associated with lower HbA1c, lower cost and less need for acute care. But in practice, FDC is not popular in China because of many reasons. One of the main arguments is that physicians think FDC lacks flexibility. Compelling evidence has shown that the co-administration of Dapagliflozin and Metformin extended-release (XR) tablets is superior to either of the monotherapy efficacy (Dapagliflozin or Metformin XR). Xigduo XR combines those two anti-hyperglycemic medicinal products with different and complementary mechanisms of action to improve glycemic control in patients with T2DM. Bioequivalence was demonstrated between FDC regimen and coadministered Dapagliflozin and Metformin HCl XR tablets. This dosage of Dapagliflozin 10 mg/Metformin hydrochloride XR 1000 mg FDC (Xigduo XR) has no clinical evidence except that bioequivalence study in China, and there are no combination therapy data available either for Chinese people. (Metformin XR usual dose is 1500-2000mg/d). Moreover, there is no head-to-head study comparing Dapa/Met FDC and co-administration therapies to the extra benefits of FDC.

Eligibility Criteria:
Inclusion Criteria:

Age and Informed Consent

1. Patient must be 18 to 80 (years of age inclusive), at the time of signing the ICF(s).

   Type of Patient and Disease Characteristics
2. Newly diagnosed T2DM (WHO diagnostic criteria 1999) ≤ 1 year with medicine treatment naïve.
3. HbA1c 7.5%-10% at screening by local lab and HbA1c 7.5-10% at pre-randomization visit (by central laboratory).
4. BMI ≥19 and ≤40 kg/m2 at screening. Other Inclusion Criteria
5. Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria:

Medical Conditions

1. Congestive heart failure NYHA classes III or IV or major cardiovascular events within 6 months before screening. (Significant cardiovascular history within the past 6 months prior to screening defined as: myocardial infarction, coronary angioplasty or bypass graft(s), valvular disease or repair, unstable angina pectoris, transient ischemic attack, or cerebrovascular accident.)
2. Patients with clinically apparent hepatobiliary disease, including but not limited to chronic active hepatitis and/or severe hepatic insufficiency. ALT or AST \> 3x ULN, or serum TB \>34.2 μmol/L (\>2 mg/dL).
3. Patients with eGFR\< 45 mL/min per 1.73 m².
4. Diagnosis or history of acute metabolic diabetic complications such as ketoacidosis or hyperglycemic hyperosmolar state, or diabetes insipidus within the past 6 months.
5. For women only - currently pregnant (confirmed with positive pregnancy test) or breastfeeding.
6. Participation in any other study that included drug treatment during the past 3 months before enrolment.

   Diagnostic Assessments
7. Patients with a known hypersensitivity to Dapa/Met or any of the excipients of the product.
8. Diagnosis or history of:

   1. Chronic pancreatitis within past 6 months or idiopathic acute pancreatitis within past 4 weeks.
   2. Gastrointestinal disease including gastroenterostomy, enterectomy, roemheld syndrome, severe hernia, intestinal obstruction, intestinal ulcer within past 6 months.
   3. Genetic galactose intolerance, lapp lactase deficiency and glucose-galactose malabsorption.
   4. Medullary thyroid carcinoma within past 5 years.
   5. Organ transplant or AIDS within the past 6 months.
   6. Alcohol abuse or illegal drug abuse within the past 12 months.
   7. Laser treatment for proliferative retinopathy within 6 months.
   8. Stress condition, such as surgery, serious trauma, etc., within past 6 months, or plan to undergo a surgery during study period.
   9. Chronic oxygen deficiency diseases, such as pulmonary emphysema, pulmonary heart disease within past 6 months.
   10. T1DM, diabetes resulting from pancreatic injury or secondary forms of diabetes, eg, acromegaly or Cushing's syndrome.

   Other Exclusions
9. Subject is, in the judgment of the Investigator, unlikely to comply with the protocol or has any severe concurrent medical or psychological condition that may affect the interpretation of study results.
10. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).