| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045242 |
| E.1.2 | Term | Type II diabetes mellitus |
|
| 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 A1C achieved with each dapagliflozin treatment group versus placebo, after 24 weeks of oral administration of double-blind treatment. |
|
| E.2.2 | Secondary objectives of the trial |
| 1) To compare the change from baseline in estimated GFR in each dapagliflozin treatment group versus placebo, after 52 weeks of oral administration of study treatment 2) To compare the change from baseline in estimated creatinine clearance (CrCl) in each dapagliflozin treatment group versus placebo, after 52 weeks of oral administration of study treatment 3) To compare the change from baseline in FPG achieved with each dapagliflozin treatment group versus placebo, after 24 weeks of oral administration of double-blind treatment 4) To compare the change from baseline in body weight achieved with each dapagliflozin treatment group versus placebo, after 24 weeks of oral administration of double-blind treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1) Subjects must be willing and able to give signed and dated written informed consent. 2) Subjects must have type 2 diabetes with inadequate glycemic control, defined as central laboratory A1C ≥ 7.0% and ≤ 11.0%. Note: A one-time central laboratory re-test of the A1C is allowed in subjects with an initial central enrollment A1C of 6.9% as determined by the Investigator. In situations where the central laboratory A1C value meets criteria for re-test, such a re-test of the A1C value is allowed provided the subject is otherwise fully eligible, as determined by the Investigator. 3) Subjects on a stable anti-diabetic regimen. A stable anti-diabetic regimen is defined as either diet and exercise therapy alone or in combination with a regimen of any approved anti-diabetic medication(s), including insulin, in which either the doses of oral anti-diabetic medications, exenatide, or pramlintide have not changed during the 6 weeks prior to enrollment; or the doses of long-acting insulin or intermediate-acting insulin have not varied by more than 20% during the 6 weeks prior to enrollment. 4) Subjects with moderate renal impairment. The degree of renal impairment is defined by the estimated GFR, according to the re-expressed abbreviated (four-variable) MDRD Study equation (see Protocol Section 4.1). Moderate renal impairment is defined as an eGFR 30 mL/min/1.73m2 to 59 mL/min/1.73m2. 5) BMI ≤ 45.0 kg/m2 at the enrollment visit. 6) Men and women, ≥ 18 years of age at the time of the enrollment visit. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized |
|
| E.4 | Principal exclusion criteria |
| 1)WOCBP unwilling or unable to use acceptable method to avoid pregnancy for entire study period 2)Pregnant or breastfeeding Women 3)Women with a positive pregnancy test on enrollment or prior to investigational product administration 4)Aspartate Aminotransferase >3X ULN 5)Alanine Aminotransferase >3X ULN 6)Total Bilirubin >2 mg/dL (34.2 μmol/L) 7)Serum Potassium >5.5 meq/L 8)Serum Phosphorus ≥6.5 mg/dL Note: one-time retest may be allowed, as determined by the Investigator, after a minimum of 2 weeks following the initiation or adjustment of phosphate binder medication. Such cases should be discussed with the Sponsor prior to re-testing the serum phosphorus 9)Serum Calcium <8 mg/dL or >ULN 10)Positive for hepatitis B surface antigen 11)Positive for anti-hepatitis C virus antibody 12)Hemoglobin ≤9.0 g/dL (90 g/L) for men; hemoglobin ≤8.0 g/dL (80 g/L) for women 13)Creatine Kinase >3X ULN 14)Abnormal free T4 values. Abnormal TSH value at enrollment will be further evaluated by free T4. Subjects with abnormal free T4 values will be excluded 15)History of diabetes insipidus 16)Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not limited to marked polyuria & polydipsia with greater than 10% weight loss during the 3 months prior to enrollment, or other signs & symptoms 17)History of diabetic ketoacidosis or hyperosmolar nonketotic coma 18)Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mmHg &/or diastolic blood pressure ≥ 110 mmHg 19)Myocardial infarction 20)Cardiac surgery or revascularization 21)Unstable angina 22)Unstable congestive heart failure 23)CHF New York Heart Association Class III or IV (See Protocol Appendix 3) 24)Transient ischemic attack or significant cerebrovascular disease 25)Unstable or previously undiagnosed arrhythmia 26)History of rapidly progressing renal disease 27)History of lupus nephritis 28)History of renal or systemic vasculitis 29)History of familial renal glucosuria 30)History of renal artery stenosis, with renovascular hypertension or ischemic nephropathy 31)History of renal transplant 32)Hemodialysis, ultrafiltration therapy, or peritoneal dialysis within 6 months prior to enrollment 33)Significant hepatic disease, including, but not limited to, chronic active hepatitis 1/or severe hepatic insufficiency 34)Documented history of hepatotoxicity with any medication 35)Documented history of severe hepatobiliary disease 36)History of hemoglobinopathy with the exception of sickle cell trait or thalassemia minor; or chronic or recurrent hemolysis 37)Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of >400 mL of blood during 6 weeks prior to enrollment visit 38)Malignancy within 5 years of enrollment visit (with exception of treated basal cell or treated squamous cell carcinoma) 39)Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for HIV 40)Allergies or contraindication to the contents of dapagliflozin tablets 41)Administration of metformin within 6 weeks of enrollment 42)Replacement or chronic systemic corticosteroid, defined as any dose of systemic corticosteroid taken for >4 weeks within 3 months prior to enrollment visit 43)History of bariatric surgery or lap-band procedure 44)Administration of sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylpropion, methamphetamine, and/or phendimetrazine, within 30 days of enrollment visit 45)Any unstable endocrine, psychiatric, or rheumatic disorders as judged by the Investigator 46)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 efficacy or safety data |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the change in A1C from baseline to Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment is available (LOCF). For rescued subjects, measurements obtained after rescue will not be considered in calculating the primary endpoint. The secondary endpoints include the change from baseline in FPG and body weight at Week 24 (LOCF), change from baseline in GFR at Week 52, and change from baseline in CrCl at Week 52 |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
| |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 1 |
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