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    EudraCT Number:2011-002231-26
    Sponsor's Protocol Code Number:D1693C00005
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-08-01
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedCzechia - SUKL
    A.2EudraCT number2011-002231-26
    A.3Full title of the trial
    A 24-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled, International Phase III Study with a 28-week Extension Period to Evaluate the Safety and Efficacy of Dapagliflozin 10mg once daily in Patients with Type 2 Diabetes who have Inadequate Glycaemic Control on a background combination of Metformin and Sulfonylurea
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of Safety and Efficacy of Dapagliflozin in subjects with Type 2 Diabetes who have Inadequate Glycaemic Control on background combination of Metformin and Sulfonylurea
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD1693C00005
    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.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.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 number001800236993
    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.3.9.1CAS number 960404-48-2
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 II 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 14.1
    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
    The primary objective of this study is to compare the change from baseline in haemoglobin A1c (HbA1c) to week 24 between dapagliflozin 10 mg in combination with metformin and sulfonylurea and placebo in combination with metformin and sulfonylurea.
    E.2.2Secondary objectives of the trial
    Key Secondary Objectives
    · To compare the change from baseline in fasting plasma glucose (FPG) to week 24 between dapagliflozin and placebo.
    · To compare the change from baseline in total body weight to week 24 between dapagliflozin and placebo.
    · To compare the proportion of patients achieving a therapeutic glycaemic response, defined as HbA1c < 7.0%, at week 24 between dapagliflozin and placebo.
    · To compare the change from baseline in seated systolic blood pressure (SBP) to week 8 between dapagliflozin and placebo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    The following criteria apply to the enrolment, placebo lead-in and randomisation visits (Visits 1, 2, 3, and 4).
    1. Provision of informed consent prior to any study specific procedures.
    2. Diagnosis of type 2 diabetes mellitus.
    3. Men or women age ≥18 years old, the upper age limit should be based on local metformin label restrictions.
    4. Stable dose combination therapy of metformin ³1500mg/day and at least half the maximum dose of a sulfonylurea for at least 8 weeks prior to enrolment.
    5. HbA1c inclusion criteria:
    · At enrolment (Visit 1) – laboratory values from screening visit:
    ≥7.7% and ≤11.0%.
    · At the randomisation visit (Visit 4) – laboratory values from visit 3:
    ≥7.0% and ≤10.5%.
    6. 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.
    E.4Principal exclusion criteria
    The following criteria apply to the enrolment, placebo lead-in and randomisation visits (Visits 1, 2, 3, and 4)
    Endocrine and metabolic disorders
    Diagnosis of Type 1 diabetes mellitus, known diagnosis of MODY or secondary diabetes mellitus
    History of diabetic ketoacidosis
    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
    FPG >270 mg/dL (>15 mmol/L) – assessed based on laboratory results from Visits 1, 2 and 3
    BMI >45 kg/m2
    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
    Diabetes insipidus
    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
    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 2 months prior to enrolment
    Less than 2 months post coronary artery revascularization prior to enrolment
    Congestive heart failure defined as New York Heart Association (NYHA) class IV, unstable or acute congestive heart failure.
    Blood pressure:
    At enrolment (Visit 1): Systolic BP ≥170 mmHg and/or diastolic BP ≥110 mmHg
    At randomisation (Visit 4): Systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg
    Kidney or urological disorders
    Measured serum creatinine value of ≥1.5 mg/dL (133 μmol/L) for male patients and ≥1.4 mg/dL (124 μmol/L) for female patients or renal function that would preclude treatment with metformin according to local guidance
    History of unstable or rapidly progressing renal disease
    Familial renal glucosuria. This condition is diagnosed as glucosuria (>1.0 mmol/L urine) in the presence of normoglycaemia in patients without the diagnosis of diabetes mellitus
    History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit, where according to the investigator a satisfactory evaluation of hematuria has not been conducted based on guidance in section
    Hepatic disorders
    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
    Total bilirubin >2.0 mg/dL (34.2 µmol/L)
    Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody
    History of drug-induced liver enzyme elevations
    History of severe hepatobiliary disease or hepatotoxicity with any medication
    Hematologic/oncologic disorders/conditions
    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
    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)
    Iron deficiency anaemia with iron therapy started in the past 12 weeks prior to enrolment visit, or a recent diagnosis of iron deficiency anaemia that requires therapeutic management within the next 24 weeks in the judgement of the investigator
    Donation or transfusion of blood, plasma, or platelets within the past 12 weeks prior to enrolment
    History of malignancy within the last 5 years prior to enrolment, excluding successful treatment of basal or squamous cell skin cancer
    Infectious disease/immunologic disorders
    Known immunocompromised status, including patients who underwent organ transplantation
    Musculoskeletal disorders
    Creatine Kinase (CK) >3x ULN
    History of drug-induced myopathy or drug-induced CK elevation
    Reproductive status
    Pregnant or breastfeeding patients
    Prohibited medications
    Use of any anti-hyperglycaemic medications other than metformin or sulfonylurea during the 10 weeks prior to enrolment
    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
    Treatment with systemic 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; Treatment with single injections of systemic glucocorticoids, topical or inhaled corticosteroids are allowed
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome variable:
    · Change in HbA1c from baseline to week 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    see E.5.1
    E.5.2Secondary end point(s)
    Key secondary outcome variables:
    · Change in fasting plasma glucose (FPG) from baseline to week 24.
    · Change in total body weight from baseline to week 24.
    · Proportion of patients achieving a therapeutic glycaemic response, defined as HbA1c <7.0% at week 24.
    · Change in seated systolic blood pressure (SBP) from baseline to week 8.
    Other secondary outcome variables:
    · Proportion of patients discontinued for lack of efficacy or rescued for failing to maintain FPG below pre-specified rescue criteria at weeks 4, 8, 16 and 24.
    · Change in HbA1c in patients with baseline HbA1c ≥8.0% from baseline to week 24.
    · Change in HbA1c in patients with baseline HbA1c ≥9.0% from baseline to week 24.
    · Change in FPG from baseline to week 8.
    · Change in seated SBP from baseline to week 24.
    · Proportion of patients with seated blood pressure of <130/80 mmHg at week 24 in patients with baseline elevated blood pressure (baseline SBP ≥130 mmHg and/or baseline diastolic blood pressure (DBP) ≥80 mmHg).
    · Percent change in fasting lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) from baseline to week 24.
    · Change in HOMA-2, HOMA-IR from baseline to week 24.
    · Change in insulin, proinsulin and C-peptide values from baseline to week 24.
    · Change in waist circumference from baseline to week 24.
    · Effect of dapagliflozin versus placebo from baseline to week 24 on health-related quality of life (HRQL) as measured by Euro quality of life 5 Dimensions 3 levels (EQ-5D-3L).
    · Scores of treatment satisfaction, individual satisfaction and perceived frequency of hyper/hypoglycaemia as measured by Diabetes Treatment Satisfaction Questionnaire status (DTSQs) at baseline, week 24 and at week 52.
    · Scores of change of treatment satisfaction, individual satisfaction and perceived frequency of hyper/hypoglycaemia using the Diabetes Treatment Satisfaction Questionnaire change (DTSQc) observed with dapagliflozin versus placebo at week 52.
    · To assess HRQL- (EQ-5D-3L), weight related quality of life (SHIELD-WQ-9, IWQOL-Lite) and treatment satisfaction (DTSQc and DTSQs) over 52 weeks of treatment.
    · Effects of dapagliflozin and placebo on weight related quality of life as measured by SHIELD-WQ-9.
    · Effects of dapagliflozin and placebo on weight related quality of life as measured by IWQOL-Lite.
    · AEs, including adjudication of CV events, laboratory values, electrocardiogram, pulse, blood pressure, hypoglycaemic events and physical examination findings.
    E.5.2.1Timepoint(s) of evaluation of this end point
    see 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. 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 No
    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 EEA40
    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
    Czech Republic
    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 years2
    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 years2
    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 No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 No
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 162
    F.4.2.2In the whole clinical trial 216
    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)
    After having completed or discontinued the study, patients will receive alternative anti-hyperglycaemic treatment according to the investigator's judgement and according to local medical practice.
    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 Decision2011-10-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-08-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-08-12
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