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    Summary
    EudraCT Number:2009-017061-28
    Sponsor's Protocol Code Number:D1690C00019
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-05-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2009-017061-28
    A.3Full title of the trial
    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 and cardiovascular disease, who exhibit inadequate glycaemic control on usual care.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Not applicable.
    A.4.1Sponsor's protocol code numberD1690C00019
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01042977
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointClinical Study Information
    B.5.4Telephone number0018002369933
    B.5.6E-mailinformation.center@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDapagliflozin
    D.3.2Product code BMS-512148
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeBMS-512148-05
    D.3.9.3Other descriptive nameDapagliflozin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    type 2 diabetes mellitus
    E.1.1.1Medical condition in easily understood language
    diabetes type II
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10012613
    E.1.2Term Diabetes mellitus non-insulin-dependent
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary objectives of the trial
    mean percent change in body weight 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

    mean change in
    seated systolic blood pressure (SBP) from baseline to wk 8 between dapagliflozin 10 mg vs placebo
    seated SBP from baseline to wk 24 between dapagliflozin 10 mg vs placebo

    change in seated SBP in patients with baseline seated SBP ≥130 mm Hg achieved with dapagliflozin vs placebo from baseline to wk 8

    28 wk extension period I
    assess the maintenance of efficacy of dapagliflozin 10 mg vs placebo over 52 wks of treatmt
    assess the safety and tolerability of dapagliflozin 10 mg over 52 wks of treatmt

    52 wk extension period II
    assess the maintenance of efficacy of dapagliflozin 10 mg vs placebo over 104 wks of treatmt
    assess the safety and tolerability of dapagliflozin 10 mg over 104 wks of treatmt
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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)
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    see above E.5.1
    E.5.2Secondary end point(s)
    Key secondary outcome variables:
    · Mean percent change in body weight 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
    · Mean change in seated systolic blood pressure from baseline to week 8
    · Mean change in seated systolic blood pressure from baseline to week 24
    · Mean change in seated systolic blood pressure from baseline to week 8 in patients with baseline seated systolic blood pressure ≥130 mmHg.
    E.5.2.1Timepoint(s) of evaluation of this end point
    see above E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Austria
    Bulgaria
    Canada
    Chile
    Germany
    Hungary
    Poland
    United States
    E.8.7Trial 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
    The end of the study is defined as ‘the last visit of the last patient undergoing the study’
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 511
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 453
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 940
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not applicable
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-03-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-12-18
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