E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Men and women with type 2 diabetes, ages ≥ 18 to ≤ 89 years, who have type 2
diabetes with inadequately controlled hypertension. |
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E.1.1.1 | Medical condition in easily understood language |
Men and women with type 2 diabetes, between 18 and 89 years old, who have type 2 diabetes with not very well controlled high blood pressure |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066860 |
E.1.2 | Term | Uncontrolled hypertension |
E.1.2 | System Organ Class | 100000004866 |
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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 seated systolic blood pressure after 12 weeks of double-blind treatment between the dapagliflozin 10 mg treatment group and the placebo treatment group.
• To compare the change from baseline in HbA1c after 12 weeks of double-blind treatment between the dapagliflozin 10 mg treatment group and the placebo treatment group. |
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E.2.2 | Secondary objectives of the trial |
To compare the change from baseline in 24 hour ambulatory systolic blood pressure after 12 weeks of doubleblind treatment between the dapagliflozin 10 mg treatment group and the placebo treatment group.
• To compare the change from baseline in seated and 24 hour ambulatory diastolic blood pressure after 12 weeks
of double-blind treatment between the dapagliflozin 10 mg treatment group and the placebo treatment group.
• To compare the change from baseline in serum uric acid after 12 weeks of double-blind treatment between the dapagliflozin 10 mg treatment group and the placebo treatment group. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subjects must have type 2 diabetes with inadequate glycemic control, defined as central laboratory HbA1c ≥ 7.0% and ≤ 10.5% obtained at the enrollment visit.
• Subjects must be on a stable dose of an OAD for at least 6 weeks (12 weeks for a TZD) or a stable daily dose of insulin, as a monotherapy or in combination with another OAD, for 8 weeks prior to enrollment and a stable effective therapeutic dose of an ACEI or an ARB for at least 4 weeks. Stable dose is defined as a dose that has remained the same for the specified number of weeks, as mentioned above, prior to the enrollment visit.
• Subjects must have inadequately controlled hypertension, defined as seated SBP ≥ 140 and < 165 mmHg AND seated DBP ≥ 85 and < 105 mmHg, each representingthe mean of three consecutive determinations, evaluated at both the enrollment and Day 1 visits.
• Subjects must have a mean 24-hour blood pressure ≥ 130/80 mmHg as determined by ambulatory blood pressure monitoring (ABPM) during lead in, measured between Day-7 and Day-1, within 1 week prior to the Day 1 randomization visit.
• C-peptide ≥ 0.8 ng/mL (0.30 nmol/L)
• BMI ≤ 45.0 kg/m2 at the enrollment visit.
• Men and women ages must be ≥ 18 and ≤ 89 years old at the time of the enrollment visit. Men and women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
• WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
• Women must not be breastfeeding. |
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E.4 | Principal exclusion criteria |
1) History of diabetes insipidus.
2) 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.
3) History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
4) History of malignant or accelerated hypertension.
5) Known or suspected secondary hypertension.
Any of the following CV/Vascular Diseases within 6 months of the enrollment visit:
6) Myocardial infarction.
7) Cardiac surgery or revascularization (coronary artery bypass surgery [CABG]/
percutaneous transluminal coronary angioplasty [PTCA]).
8) Unstable angina.
9) Unstable congestive heart failure (CHF).
10) CHF New York Heart Association (NYHA) Class III or IV. (see Appendix 1)
11) Transient ischemic attack (TIA) or significant cerebrovascular disease.
12) Unstable or previously undiagnosed arrhythmia.
Metabolic Diseases
13) Under revised protocol #4 subjects with a History of Gout may be entered into the study.
14) History of unstable or rapidly progressing renal disease.
15) Conditions of congenital renal glucosuria.
16) Renal allograft
17) Significant hepatic disease, including but not limited to, chronic active hepatitis and/or severe hepatic insufficiency
18) Documented history of hepatotoxicity with any medication.
19) Documented history of severe hepatobiliary disease
20) History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis.
21) 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.
22) Malignancy within 5 years of the enrollment visit (with the exception of treated basal cell or treated
squamous cell carcinoma of the skin).
23) Known immunocompromised status, including but not limited to, individuals who
have undergone organ transplantation or who are positive for the human immunodeficiency virus.
Central Laboratory Test Findings at Enrollment
24) Aspartate Aminotransferase (AST) > 3X Upper limit of normal (ULN).
25) Alanine aminotransferase (ALT) > 3X ULN.
26) Serum total bilirubin (TB) ≥ 1.5X ULN
27) Serum Creatinine (SCr) ≥ 2.0 mg/dL unless subject is on metformin then the exclusionary limits will be SCr ≥ 1.50 mg/dL (133 μmol/L) for male subjects; SCr ≥ 1.40 mg/dL (124 μmol/L) for female subjects
28) Estimated creatinine clearance (Crcl) of < 60ml/min
29) Hemoglobin ≤ 10.0 g/dL (100 g/L) for men; hemoglobin ≤ 9.0 g/dL (90 g/L) for women.
30) Creatine kinase (CK) > 3X ULN.
31) Positive for hepatitis B surface antigen.
32) Positive for anti-hepatitis C virus antibody.
33) Abnormal free T4 value.
34) Allergies or contraindication to the contents of dapagliflozin tablets.
35) Obesity that would limit accurate blood pressure measurement
36) History of bariatric surgery or lap-band procedure.
37) Administration of sibutramine, phentermine, rimonabant, benzphetamine, diethylpropion, methamphetamine,
orlistat, and/or phendimetrazine.
38) Prisoners or subjects who are involuntarily incarcerated.
39) Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness.
40) Replacement or chronic systemic corticosteroid therapy, defined as any dose of
systemic corticosteroid taken for > 4 weeks within 3 months prior to enrollment visit.
NOTE: Topical or inhaled corticosteroids are allowed.
41) Any unstable endocrine, psychiatric, rheumatic disorders as judged by the Investigator.
42) 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.
43) Subject with any condition which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject
44) Subject is currently abusing alcohol or other drugs or has done so within the last 6 months.
45) Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned
46) Previous participation in a clinical trial with dapagliflozin (BMS-512148) and/or with any other SGLT2 inhibitors.
47) Administration of any other investigational drug within 30 days of planned enrollment to this study |
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E.5 End points |
E.5.1 | Primary end point(s) |
The co-primary endpoints are the change in seated systolic blood pressure and the change in HbA1c from baseline at Week 12, or the last post-baseline measurement prior to Week 12, if no Week 12 assessment is available. For subjects rescued for hypertension, measurements obtained after initiation of rescue medication will not be considered in calculating the co-primary endpoint of seated systolic blood pressure. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints include the change in 24 hour ambulatory systolic blood pressure from baseline at Week 12, or the last post-baseline measurement prior to Week 12, if no Week 12 assessment is available, the change in seated and 24 hour ambulatory diastolic blood pressure from baseline at Week 12, or the last post-baseline measurement
prior to Week 12, if no Week 12 assessment is available and the change in serum uric acid from baseline at Week 12, or the last post-baseline measurement prior to Week 12, if no Week 12 assessment is available. For subjects rescued for hypertension, measurements obtained after initiation of rescue medication will not be considered in calculating the secondary endpoints of 24 hour ambulatory systolic blood pressure and seated and 24 hour ambulatory diastolic blood pressure. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 101 |
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 | No |
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 |
Colombia |
Czech Republic |
Denmark |
Finland |
Germany |
Hungary |
India |
Ireland |
Mexico |
Peru |
Poland |
Puerto Rico |
Russian Federation |
Spain |
United Kingdom |
United States |
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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
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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 | |
E.8.9.1 | In the Member State concerned months | |
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 | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |