not applicable

• Register: EUCTR
• Last refreshed on: 10 June 2013
• Main ID: EUCTR2009-016791-71-DE
• Date of registration: 28/12/2009
• Prospective Registration: Yes
• Primary sponsor: AstraZeneca AB
• Public title: not applicable
• Scientific title: A 24-week, multicentre, randomised, double-blind, age-stratified, placebo controlled phase III study with an 80-week extension period to evaluate the efficacy and safety of dapagliflozin 10 mg once daily in patients with type 2 diabetes, cardiovascular disease and hypertension, who exhibit inadequate glycaemic control on usual care.
• Date of first enrolment: 07/04/2010
• Target sample size: 1175
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-016791-71
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Argentina, Canada, Germany, Romania, Slovakia, Spain, Taiwan, Vietnam

Contacts

• Name: Clinical Study Information
• Affiliation: AstraZeneca

• Name: Clinical Study Information
• Affiliation: AstraZeneca

Key inclusion & exclusion criteria

Inclusion criteria:
Inclusion criteria at enrolment (Visit 1) and start of placebo lead-in (Visits 2).
1.Provision of informed consent prior to any study specific procedures
2.Prior diagnosis of type 2 diabetes
3.Age at enrolment visit
-Men =45 years old
-Women =50 years old
4.Anti-hyperglycaemic treatment should have been used uninterrupted on a daily basis for 8 weeks and stable for at least 4 weeks before enrolment and identical to one of the defined.
5.At enrolment: 7.2% =HbA1c =10.5% (sample will be taken at screening)
6.Cardiovascular disease as defined.
7.Hypertension as defined
8.For patients on anti-hypertensive treatment, the anti-hypertensive treatment should have been used uninterrupted on a daily basis in the last 4 weeks before the enrolment.
9.Women not of childbearing potential or women of childbearing potential who comply with defined criteria

Inclusion criteria at randomisation (visit 4, laboratory values from visit 3):
Subject Patients should fulfil inclusion criteria number 1 to 9 (listed above) and the following criteria at randomisation:
10. HbA1c =7.0% and =10.0% at randomisation (value from blood sample obtained at Visit 3).
11. Uninterrupted monotherapy or dual combination therapy of oral diabetes drugs (with or without insulin) for at least 12 weeks before randomisation.
12. Insulin treatment for at least 12 weeks randomisation, if administered.
13. The dose of anti-hyperglycaemic drugs and the insulin regimen should be stable for 8 weeks before randomisation.
14. For patients on current anti-hypertensive treatment the administration of anti-hypertensive drug(s) should be uninterrupted for 8 weeks before randomisation and dose should be stable for 4 weeks before randomisation.
15. Lipid-lowering and/ or anti-platelet treatment should be uninterrupted for 4 weeks before randomisation, if administered.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 527
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 395

Exclusion criteria:
The following criteria apply to the enrolment, placebo lead in and randomisation visits (Visits 1, 2, and 4).
Endocrine and metabolic disorders
1. Diagnosis of Type 1 diabetes mellitus, known diagnosis of MODY or secondary diabetes mellitus
2. Use of 3 or more oral anti-hyperglycaemic drugs with or without insulin
3. History of diabetic ketoacidosis
4. 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
5. FPG >270 mg/dl (>15 mmol/L) at randomisation (sample will be taken at visit 3)
6. History of bariatric surgery (ie, any surgery to treat obesity; for example, gastric banding or procedures that involve bypassing or transposing sections of the small intestine). History of liposuction is allowed.
7. Diabetes insipidus
8. Thyroid-stimulating hormone (TSH) and free T4 values outside normal range. An abnormal TSH value needs to be followed up with a free T4 test. Patients with abnormal free T4 values will be excludedCardiovascular disorders
9. Recent Cardiovascular Events in a patient:
- Acute Coronary Syndrome (ACS) within 2 months prior to enrolment
- Hospitalization for unstable angina or acute myocardial infarction within 2 months prior to enrolment
- Acute Stroke or TIA within two months prior to enrolment
- Less than two months post coronary artery revascularization
10. Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure. Note: eligible patients with congestive heart failure, especially those who are on diuretic therapy, should have careful monitoring of their volume status throughout the study.
11. Blood pressure:
- At enrolment (Visit 1):
Systolic BP =165 mmHg and/or diastolic BP =100 mmHg
- At randomisation (Visit 4):
Systolic BP =160 mmHg and/or diastolic BP =100 mmHg
Kidney disorders
12. Calculated creatinine clearance <60 mL/min
13. Urine albumin: creatinine ratio (UACR) >1800 mg/g (>203.4 mg/mmol/L)
14. History of unstable or rapidly progressing renal disease
15. Familial renal glucosuria. This condition is diagnosed as glucosuria (>1.0 mmol/L urine) in the presence of normoglycaemia in a patients without the diagnosis of diabetes mellitus
Hepatic disorders
16. Severe hepatic insufficiency and/or significant abnormal liver function defined as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
17. Total bilirubin >2.0 mg/dL (34.2 µmol/L)
18. Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody
19. History of drug-induced liver enzyme elevations
20. History of severe hepatobiliary disease or hepatotoxicity with any medication
Hematologic/oncologic disorders/conditions
21. Haemoglobin <10 g/dL (<100 g/L) or 6.2 mmol/L for men; haemoglobin <9.0 g/dL (<90 g/L) or 5.9 mmol/L for women
22. History of chronic haemolytic anaemia or haemoglobinopathies (for example, sickle cell anaemia, thalassemia, sideroblastic anemia). Mild haemolysis due to artificial heart valves is not an exclusion criterion except when haemoglobin levels are too low
23. Donation or transfusion of blood, plasma, or platelets within the past 3 months prior to Visit 1
24. History of malignancy within the last 5 years, excluding successful treatment of basal or s

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

type 2 diabetes mellitus
MedDRA version: 14.0 Level: LLT Classification code 10012613 Term: Diabetes mellitus non-insulin-dependent System Organ Class: 10027433 - Metabolism and nutrition disorders

Intervention(s)

Product Name: Dapagliflozin
Product Code: BMS-512148
Pharmaceutical Form: Film-coated tablet
Current Sponsor code: BMS-512148-05
Other descriptive name: Dapagliflozin
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: 2 independent primary objectives of equal weight:
•To compare the glycaemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension, measured as the mean change in haemoglobin A1c (HbA1c) from baseline to week 24, in the overall population and in the two predefined age subgroups (<65 years, =65 years).
•To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as:
-an absolute drop of 0.5% or more from baseline HbA1c, and
-a relative drop of 3% or more from baseline for total body weight, and
-an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure, in the overall population and in the two predefined age subgroups (<65 years, =65 years).

Primary end point(s): All efficacy variables will be evaluated in the overall population and in the two predefined age subgroups (<65years, =65years).
Primary outcome variables:
· Mean change in HbA1c from baseline to week 24
· Proportion of responders meeting all criteria of a 3-item endpoint of clinical benefit after 24 weeks of treatment, defined as:
- an absolute drop of 0.5% or more from baseline HbA1c, and
- a relative drop of 3% or more from baseline for total body weight, and
- an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.

Timepoint(s) of evaluation of this end point: see above E.5.1

Secondary Objective: mean change in seated systolic blood pressure (SBP) from baseline to wk 8 between dapagliflozin 10 mg vs placebo
mean percent change in body weight from baseline to wk 24 between dapagliflozin 10 mg vs placebo
mean change in seated SBP from baseline to wk 24 between dapagliflozin 10 mg vs placebo
proportion of pts with BMI baseline =27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg vs placebo from baseline to wk 24

28-week extension period I
assess maintenance of efficacy of dapagliflozin 10 mg vs placebo over 52 wks of treatmt
assess safety and tolerability of dapagliflozin 10 mg over 52 wks of treatmt
52-week extension period II
assess maintenance of efficacy of dapagliflozin 10 mg vs placebo over 104 wks of treatmt
assess safety and tolerability of dapagliflozin 10 mg over 104 wks of treatmt

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: see above E.5.2

Secondary end point(s): Key secondary outcome variables:
· Mean change in seated systolic blood pressure from baseline to week 8
· Mean percent change in body weight from baseline to week 24
· Mean change in seated systolic blood pressure from baseline to week 24
· Proportion of patients with baseline BMI =27 kg/m2 with a reduction from baseline of 5% or more in body weight from baseline to week 24

Secondary ID(s)

NCT01031680

D1690C00018

Source(s) of Monetary Support

AstraZeneca