| 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 | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067585 |
| E.1.2 | Term | Type 2 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 |
Research Hypothesis: There is no formal research hypothesis for this study. This study will evaluate the percent change from baseline in GFR with dapagliflozin plus metformin and/or a sulfonylurea (SU) versus placebo plus metformin and/or SU, after 12 weeks of oral double-blind treatment.
This study has no primary or secondary objectives. |
|
| E.2.2 | Secondary objectives of the trial |
| This study has no primary or secondary objectives. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy exploratory objective:
− To assess the percent change from baseline in red cell mass (RCM) and plasma volume (PV) achieved with dapagliflozin 10 mg plus metformin and/or SU versus HCTZ 25 mg plus metformin and/or SU, after 12 weeks of oral administration of double-blind treatment
− To assess the percent change from baseline in RCM and PV achieved with dapagliflozin 10 mg plus metformin and/or SU versus placebo plus metformin and/or SU, after 12 weeks of oral administration of double-blind treatment. |
|
| 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 HbA1c ≥ 6.6% and ≤ 9.5% obtained at the enrollment visit.
3) Subjects should have been receiving metformin (XR or IR) and/or SU for at least 4
weeks prior to enrollment at any stable dose. Stable dose is defined as a dose that has remained the same for at least 4 weeks prior to the enrollment visit (i.e., same
prescribed total daily dose).
4) Subjects must have inadequate BP control, defined as seated SBP ≥ 130 and < 165 mmHg AND/OR seated DBP ≥ 80 and < 105 mmHg, each representing the mean of 3 consecutive determinations, evaluated at both the enrollment and Day -7
visits.
5) C-peptide ≥ 0.8 ng/ml (0.27 nmol/L) at the enrollment visit, based on central
laboratory value.
6) BMI ≤ 45.0 kg/m2 at the enrollment visit.
7) Men and women, ages ≥ 18 to ≤ 70 years old 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.
WOCBP include any female who has experienced menarche and who has not
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or is not postmenopausal. Post menopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause or
• For women with irregular menstrual periods and on hormone replacement
therapy (HRT), a documented serum follicle stimulating hormone (FSH) level
≥ 35 mIU/mL |
|
| E.4 | Principal exclusion criteria |
1) WOCBP who are unwilling or unable to use an acceptable method to avoid
pregnancy for the entire study period.
2) Women who are pregnant or breastfeeding.
3) Women with a positive pregnancy test on enrollment or prior to investigational
product administration and/or injection of iohexol, and, for subjects participating in
the substudy, prior to administration of radioisotopes for determination of RCM and
PV.
4) Estimated GFR (eGFR) by the Modification of Diet in Renal Disease (MDRD) formula ≤ 60 mL/min/1.73m2 and ≥ 150 mL/min/1.73m2.
5) Urine albumin to creatinine ratio (UACR) ≥ 300 mg/g (33.9 mg/mmol/Cr).
6) Aspartate Aminotransferase (AST) > 3X Upper limit of normal (ULN).
7) Alanine aminotransferase (ALT) > 3X ULN.
8) Serum Total Bilirubin > 2 mg/dL (34.2 μmol/L).
9) Serum Creatinine (Scr) ≥ 1.50 mg/dL (133 μmol/L) for men; SCr ≥ 1.40 mg/dL
(124 μmol/L) for women.
10) Hemoglobin ≤ 10.0 g/dL (100 g/L) for men; hemoglobin ≤ 9.0 g/dL (90 g/L) for
women.
11) Creatine kinase (CK) > 3X ULN.
12) Positive for hepatitis B surface antigen.
13) Positive for anti-hepatitis C virus antibody.
14) Abnormal free T4 value.
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 and polydipsia with greater than 10% weight loss during the 3 months prior to enrollment, or other signs and symptoms.
17) History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
18) Myocardial infarction.
19) Cardiac surgery or revascularization (coronary artery bypass surgry [CABG]/
percutaneous transluminal coronary angioplasty [PTCA]).
20) Unstable angina.
21) Unstable congestive heart failure (CHF).
22) CHF New York Heart Association (NYHA) Class III or IV. (see Appendix 3 of the protocol)
23) Transient ischemic attack (TIA) or significant cerebrovascular disease.
24) Unstable or previously undiagnosed arrhythmia.
25) History of malignant or accelerated hypertension.
26) History of gout.
27) History of unstable or rapidly progressing renal disease.
28) Conditions of congenital renal glucosuria.
29) Significant hepatic disease, including but not limited to, chronic active hepatitis
and/or severe hepatic insufficiency.
30) Documented history of hepatotoxicity with any medication.
31) Documented history of severe hepatobiliary disease.
32) History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis.
33) 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 the
6 weeks prior to the enrollment visit.
34) Malignancy within 5 years of the enrollment visit (with the exception of treated basal cell or treated squamous cell carcinoma of the skin).
35) Known immunocompromised status, including but not limited to, individuals who
have undergone organ transplantation or who are positive for the human immunodeficiency virus.
36) Allergies or contraindication to the contents of dapagliflozin tablets.
37) History of adverse reaction to radio-contrast dye.
38) Allergy or contraindication to use of thiazide diuretics.
39) Administration of insulin or any other antihyperglycemic therapy (other than
metformin and/or SU), at any dose and time, during the 4 weeks prior to the
enrollment visit.
40) Administration of any diuretics or other drugs approved for the treatment of
hypertension (with the exception of either ACEI or ARB), at any dose and time,
during the 12 weeks prior to the enrollment visit.
41) Administration of both ACEI and ARB.
42) Replacement or chronic systemic corticosteroid therapy, defined as any dose of
systemic corticosteroid taken for > 4 weeks within 3 months prior to enrollment visit.
For Other Exclusion Criteria, see protocol section 4.2.2. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the percent change from baseline in GFR, as determined by plasma clearance of nonradioactive iohexol, after 12 weeks of dapagliflozin administration. |
|
| 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 | No |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| 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 | 1 |
| 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 |
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