Type 2 Diabetes Mellitus (T2DM)
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGXigduo (Dapagliflozin and Metformin hydrochloride extended-release) tablets
10 mg Dapagliflozin/1000 mg Metformin HCl extended-release
DRUGDapagliflozin tablets and Metformin HCl extended-release tablets
Dapagliflozin tablets: 10 mg Metformin HCl extended-release tablets: 1000 mg
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in HbA1c from baseline | 24 weeks | To demonstrate non-inferiority of Dapa/Met FDC regimen when compared with Dapa + Met co-administered with respect to the primary efficacy endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute change in FPG from baseline to week 24. | 24 weeks | To describe the changes from baseline at Week 24 in fasting plasma glucose (FPG). |
| Absolute change in PPG from baseline to week 24. | 24 weeks | To describe the changes from baseline at Week 24 in postprandial glucose (PPG). |
| Proportion of patients achieved HbA1c less than 7.0% from baseline to week 24. | 24 weeks | To describe the changes from baseline at Week 24 in proportion of patients with HbA1c \< 7%. |
| The difference in quality of life between 2 groups measured with Diabetes Quality of Life (DQOL) questionnaire at week 12 and week 24. | Week 12 and Week 24 | To evaluate the difference in quality of life of FDC versus co-administered dual therapy in Chinese patients with T2DM. DQOL-Satisfaction: the minimum value is 15, the maximum value is 75, higher scores mean a worse outcome. DQOL-Impact: the minimum value is 20, the maximum value is 100, higher scores mean a worse outcome. DQOL-Worry: the minimum value is 11, the maximum value is 55, higher scores mean a worse outcome. |
| To evaluate the difference in adherence of FDC versus co-administered dual therapy by Morisky Medication Adherence Scale-8 (MMAS-8) questionnaire in Chinese patients with T2DM. | Week 24 | To evaluate the difference in adherence of FDC versus co-administered dual therapy in Chinese patients with T2DM. The minimum value is 0, the maximum value is 8, higher scores mean a better outcome. |
| The difference in satisfaction scores between 2 groups measured with the Diabetes Treatment Satisfaction Questionnaire (DTSQ) at week 24. | Week 24 | To evaluate the difference in satisfaction of FDC versus co-administered dual therapy in Chinese patients with T2DM. The minimum value is 0, the maximum value is 36, higher scores mean a better outcome. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Weight | 24 weeks | Weight in kilograms |
| Height | 24 weeks | Height in meters |
| BMI | 24 weeks | BMI in kg/m\^2 |
| Number of participants with abnormal ECG readings | 24 weeks | The normality/abnormality of ECG tracings, as determined by the Investigator. |
| Proportion of TITR (Time in Tight Target Range) | Week 12 | The percentage of readings and time that a person spends with their blood glucose levels in a Tight target range (3.9-7.8mmol/L). |
| AEs | 24 weeks | An AE can therefore be any unfavourable and unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease temporally associated with the use of a medicinal product, whether it's considered related to the medicinal product. |
| TBR (Time Below Range) | Week 12 | The percentage of readings and time that a person spends with their blood glucose levels below target range. |
| TAR (Time Above Range) | Week 12 | The percentage of readings and time that a person spends with their blood glucose levels above target range. |
| MAGE (Mean Amplitude of Glycemic Excursion) | Week 12 | The mean of blood glucose values exceeding one SD from the 24-hour mean blood glucose and is used as an index of glycemic variability. |
| SDBG (Standard Deviation of Blood Glucose) | Week 12 | SDBG (Standard Deviation of Blood Glucose), reflects the amount of variation or dispersion of a series of glucose values. |
| TIR (Time In Range) | Week 12 | The percentage of readings and time that a person spends with their blood glucose levels in a target range (3.9-10mmol/L). |
| SAE | 24 weeks | An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow up), that fulfils one or more of the following criteria: Results in death. Is immediately life-threatening. Requires in-patient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability or incapacity. Is a congenital anomaly or birth defect. Is an important medical event that may jeopardize the participant or may require medical treatment to prevent one of the outcomes listed above. |
| ADRs | 24 weeks | An Adverse Drug Reaction (ADR) is an Adverse Event suspected to be causally related to the medicinal product. |
| Temperature | 24 weeks | Armpit Temperature. |
| Systolic and diastolic BP | 24 weeks | Blood pressure should be measured with a completely automated device in triplicate with at least 1-minute intervals between measurements after being comfortably at rest in a seated position(mmHg). |
| Pulse rate | 24 weeks | Pulse rate should be measured with a completely automated device in triplicate with at least 1-minute intervals between measurements after being comfortably at rest in a seated position(times/min) |
| Respiratory rate | 24 weeks | Respiratory rate per minute(times/min) |
Countries
China
Outcome results
None listed