| 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 | 12.1 |
| 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 |
2 independent primary objectives of equal weight in this study:
· To compare the glycaemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, 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 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).
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| E.2.2 | Secondary objectives of the trial |
In the overall population and in the two predefined age subgroups (<65 years, ≥65 years) compare:
the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.
the proportion of patients with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24.
the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.
the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.
the change in seated systolic blood pressure (SBP) in patients with baseline seated SBP ≥130 mm Hg achieved with dapagliflozin versus placebo from baseline to week 8.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 following:
- Monotherapy or dual combination therapy with oral anti-diabetic drug(s) for example metformin, pioglitazone, sulfonylurea, acarbose, or a DPP-4 inhibitor (saxagliptin, sitagliptin, vildagliptin), except rosiglitazone which is not allowed for at least 8 weeks before enrolment (refer to Section 4.2, exclusion criteria 29), or
- Insulin therapy in combination with oral anti-hyperglycaemic therapy, or
- Insulin monotherapy
5. At enrolment: 7.2% ≤HbA1c ≤10.5% (value from blood sample obtained at screening)
6. Cardiovascular disease, defined as:
-Prior documented Coronary Heart Disease
-History of myocardial infarction or
-History of revascularization, or coronary artery stenosis >50%, confirmed with angiography or
-Abnormal imaging at stress test, compatible with ischemia or prior myocardial infarction or
- Prior documented Stroke or TIA, or
- Prior documented Peripheral Artery Disease (PAD) treated with revascularization (amputation is not accepted)
7. Patients who use anti-hypertensive medication (diuretics, beta blockers, ace-inhibitors, angiotensin receptor blockers, or calcium channel antagonists, and drugs that are known to have a blood pressure lowering effect, for example, medication used in treatment of congestive heart failure), should have used their medication uninterrupted on a daily basis in the last 4 weeks before the enrolment.
8. For Women only:
Women not of childbearing potential or women of childbearing potential who comply with the following:
- Use a highly effective method of birth control (see below) to avoid pregnancy throughout the study and for up to 4 weeks after the study
- Have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study medication and at each visit
Inclusion criteria at randomisation (visit 4, laboratory values from visit 3):
Patients should fulfil inclusion criteria 1 to 8(listed above) and the following criteria at randomisation:
9. HbA1c ≥7.0% and ≤10.0% at randomisation (value from blood sample obtained at Visit 3).
10. Uninterrupted monotherapy or dual combination therapy of oral diabetes drugs (with or without insulin) for at least 12 weeks before randomisation.
11. Insulin treatment for at least 12 weeks before randomisation, if administered.
12. The dose of anti-hyperglycaemic drugs and the insulin regimen should be stable for 8 weeks before randomisation.
13. The use of anti-hypertensive medication in patients - including diuretics and drugs that are known to have a blood pressure lowering effect, for example, medication used in treatment of congestive heart failure - should be uninterrupted for 8 weeks before randomisation and the dose should be stable for 4 weeks before randomisation.
14. Lipid lowering and/ or anti-platelet treatment should be uninterrupted for 4 weeks before randomisation, if administered.
For inclusion in the optional genetic research, patients must fulfil the following criterion:
15. Provision of informed consent for genetic research
If a patient declines to participate in the optional genetic research, there will be no penalty or loss of benefit to the patient. The patients will not be excluded from other aspects of the study described in this Clinical Study Protocol, as long as they consent. |
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| E.4 | Principal 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 excluded
Cardiovascular 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 anaemia). Mild haemolysis due to artificial heart valves or due to sickle cell trait is not an exclusion criterion except when haemoglobin levels are too low (as defined in haemoglobin criteria above).
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 squamous cell skin cancer
Infectious disease/immunologic disorders
25. Known immunocompromised status, including patients who underwent organ transplantation
Musculoskeletal disorders
26. Creatine Kinase (CK) >3X ULN
27. History of drug-induced myopathy or drug-induced CK elevation
Reproductive status
28. Pregnant or breastfeeding patients
Prohibited medications
29. Rosiglitazone during 12 weeks prior to randomization
30. Use of 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. Treatment with glucocorticoids equivalent to oral prednisolone ≥10 mg (betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day within 30 days prior to enrolment; topical or inhaled corticosteroids are allowed
32. Treatment with unstable doses of teriparatide, bisphosphonates and/or calcitonin (note: teriparatide, bisphosphonates and calcitonin are allowed provided the dose has not changed within 30 days prior to enrolment)
33. Treatment for Human Immunodeficiency Virus (HIV) and/or use of antiviral drugs (delavirdine, indinavir, nelfinavir, ritonavir, saquinavir)
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| E.5 End points |
| E.5.1 | 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.
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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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 study 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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