E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10012613 |
E.1.2 | Term | Diabetes mellitus non-insulin-dependent |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the change from baseline in haemoglobin A1c at 24 weeks between dapagliflozin and placebo in patients with type 2 diabetes who are inadequately controlled on sitagliptin alone or on sitagliptin plus metformin. |
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E.2.2 | Secondary objectives of the trial |
To assess effect on: total body weight – fasting plasma glucose – 2-hour post liquid meal glucose – blood pressure − glycaemic control – lipid metabolism; To assess, in a sub-population, the effect on: seated systolic blood pressure – haemoglobin A1c; To evaluate the safety and tolerability by assessment of adverse events, laboratory values, electrocardiogram, pulse, blood pressure, hypoglycaemic events, calculated creatinine clearance, estimated glomerular filtration rate and physical examination findings over 24 weeks of treatment; To collect and store DNA for future exploratory genetic research studies; Objectives of the 24-week extension period: − to assess the maintenance of efficacy of dapagliflozin versus placebo over 48 weeks of treatment − to assess the safety and tolerability of dapagliflozin over 48 weeks of treatment. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures 2. Diagnosis of type 2 diabetes 3. Men or women age ≥18 years old (for patients taking metformin, the upper age limit should be based on local metformin label restrictions) 4. Current antihyperglycaemic treatment: (a) Drug naïve (defined as no antihyperglycaemic therapy for at least 10 weeks prior to enrolment), or (b) Ongoing treatment with sitagliptin monotherapy 100 mg QD for at least 10 weeks prior to enrolment, or (c) Ongoing treatment with vildagliptin monotherapy 50 mg BID for at least 10 weeks prior to enrolment, or (d) Ongoing treatment with metformin IR or XR monotherapy ≥1500 mg/day at a stable dose for at least 10 weeks prior to enrolment, or (e) Ongoing treatment with metformin IR or XR ≥1500 mg/day at a stable dose plus sitagliptin 100 mg/day for at least 10 weeks prior to enrolment, or (f) Ongoing treatment with metformin IR or XR ≥1500 mg/day at a stable dose plus vildagliptin 50 mg BID for at least 10 weeks prior to enrolment. Treatment with OADs other than those listed above within the 10 weeks prior to enrolment is not permitted. Criteria a, b and c are not applicable in countries where DPP-IV inhibitors are not approved as monotherapy. Criteria a and b not applicable in countries where stiagliptin montherapy is approved for patients who are not eligible for metformin due to contraindications or intolerance. Investigators must confirm that patients who are receiving sitagliptin montherapy at enrolment qualify for sitagliptin montherapy. 5. HbA1c: At enrolment (Visit 1) − ≥7.2% and ≤10.0% for patients entering the study on sitagliptin100 mg QD or vildagliptin 50 mg BID monotherapy, sitagliptin 100 mg QD plus metformin ≥1500 mg/day or vildagliptin 50 mg BID plus metformin ≥1500 mg/day − ≥7.7% and ≤10.5% for patients who are drug naïve or who are treated with metformin ≥1500 mg/day monotherapy. At randomisation: ≥7.0% and ≤10.0% for all patients. 6. Women of childbearing potential who comply with defined criteria. |
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E.4 | Principal exclusion criteria |
1. Diagnosis of Type 1 diabetes mellitus, known diagnosis of MODY or secondary diabetes mellitus 2. History of diabetic ketoacidosis 3. Symptoms of poorly controlled diabetes including, but not limited to, marked polyuria, polydipsia, and/or greater than 10% weight loss during the 3 months prior to enrolment 4. FPG >270 mg/dL (>15 mmol/L) 5. History of bariatric surgery 6. Diabetes insipidus 7. Thyroid-stimulating hormone (TSH) values outside normal range 8. Creatinine clearance (Calculated Creatinine Clearance <50 mL/min calculated by Cockroft-Gault formula for patients not taking metformin, further specified for patients taking metformin; 9. Urine albumin: creatinine ratio >1800 mg/g (>203.4 mg/mmol)) 10. History of unstable or rapidly progressing kidney disease 11. Known condition of familial renal glucosuria 12. AST >3 xULN and/or ALT >3 x ULN 13. Total bilirubin >2.0 mg/dL (>34.2 μmol/L) 14. Current infectious liver disease 15. History of drug-induced liver enzyme elevations 16. History of severe heptobiliary disease or hepatotoxicity 17. Congestive heart failure NYHA class IV, unstable or acute congestive heart failure 18. Significant cardiovascular history within the past 3 months prior to the screening visit (myocardial infarction, unstable angina pectoris, transient ischemic attack, unstable or previously undiagnosed arrhythmia, cardiac surgery or revascularization, cerebrovascular accident), unstable cardiovascular disease at enrolment as judged by investigator 19. Systolic BP ≥170 mmHg and/or diastolic BP ≥110 mmHg 20. Haemoglobin ≤10 g/dL (≤100 g/L) for men; haemoglobin ≤9.0 g/dL (≤90 g/L) for women 21. History of chronic haemolytic anaemia or haemoglobinopathies 22. Donation or transfusion of blood, plasma or platelets within past 3 months 23. History of maliganacy within last 5 years 24. Known immunocompromised status 25. Creatinine Kinase >3X ULN 26. History of drug-induced myopathy or drug-induced CK elevation 27. Pregnant or breastfeeding patients 28. Use of: antihyperglycaemic medications other than DPP-4 inhibitors or metformin during the 10 weeks prior to enrolment 29. Insulin within 24 weeks of enrolment (with exceptions) 30. Weight loss medication (including but not limited to sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylproprion, methamphetamine, and/or phendimetrazine) within 30 days prior to enrolment 31. Glucocorticoids equivalent to oral prednisolone ≥10 mg (betametasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day within 30 days prior to enrolment 32. Unstable doses of teriparatide, bisphosphonates and/or calcitonin 33. Treatment for HIV and/or use of antiviral drugs 34. Intolerance, contraindication or potential allergy or hypersensitivity to dapagliflozin, metformin, sitagliptin, glimepiride, other sulfonylurea, sulphonamides, placebo or formulation excipients 35. Any clinically significant abnormality 36. Patients at risk of dehydration 37. Acute or chronic metabolic acidosis 38. History of alcohol abuse or illegal drug use within past 12 months 39. Involvement in the planning or conduct of the study 40. Previous enrolment or randomisation in present study 41. Previous participation in dapagliflozin and or other SGLT2 inhibitor study 42. Participation in another study during last month |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome variable: Change in haemoglobin A1c from baseline to week 24 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the trial is defined as 'the last visit of the last patient undergoing the study'. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |