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    EudraCT Number:2013-000239-28
    Sponsor's Protocol Code Number:D1693C00001
    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:2013-05-31
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedBulgarian Drug Agency
    A.2EudraCT number2013-000239-28
    A.3Full title of the trial

    Dapagliflozin Effect on Cardiovascular Events

    A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in Patients with Type 2 Diabetes
    Ефект на дапаглифлозин върху сърдечно-съдовите събития.
    Многоцентрово, рандомизирано, двойно-сляпо, плацебо-контролирано изпитване за оценка ефекта на дапаглифлозин 10мг. веднъж дневно върху появата на сърдечно-съдова смърт, миокарден инфаркт или исхемичен инсулт при пациенти с диабет тип 2.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study is being carried out to evaluate the effect of a drug called dapagliflozin when added to current treatment for type 2 diabetes on cardiovascular events.
    Това изпитване се провежда, за да се оцени ефекта върху сърдечно-съдовите събития на лекарство, наречено дапаглифлозин, прибавено към настоящата терапия за лечение на ЗДТ2.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberD1693C00001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01730534
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Address1800 Concord Pike, PO Box 15437
    B.5.3.2Town/ cityWilmington
    B.5.3.3Post code19850-5437
    B.5.3.4CountryUnited States
    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 Yes
    D. name Forxiga
    D. of the Marketing Authorisation holderAstraZeneca AB
    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.3.8INN - Proposed INNdapagliflozin
    D.3.9.1CAS number 960404-48-2
    D.3.9.2Current sponsor codeBMS-512148-05
    D.3.9.4EV Substance CodeSUB90205
    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 2 Diabetes mellitus
    Захарен Диабет Тип 2
    E.1.1.1Medical condition in easily understood language
    Diabetes Type 2
    Диабет Тип 2
    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 20.0
    E.1.2Level SOC
    E.1.2Classification code 10027433
    E.1.2Term Metabolism and nutrition disorders
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    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
    The primary objective is to determine the effect of dapagliflozin relative to placebo on cardiovascular outcome when added to current background therapy in patients with type 2 diabetes mellitus (T2DM) with either established cardiovascular disease or at least two cardiovascular risk factors.

    Първичната цел е да се установи ефекта на дапаглифлозин, сравнен с плацебо, върху сърдечно-съдовите събития, когато е добавен към стандартната терапия при пациенти със ЗДТ2 и с: установено сърдечно съдово заболяване или с налични поне два сърдечно-съдови рискови фактори.
    E.2.2Secondary objectives of the trial
    The secondary objective is to determine whether treatment with dapagliflozin relative to placebo when added to current background therapy in patients with type 2 diabetes mellitus (T2DM) with either established cardiovascular disease or at least two cardiovascular risk factors results in a reduction of:
    - Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 ml/min/1.73m2 and/or ESRD (dialysis ≥90 days or kidney transplantation, confirmed sustained eGFR of <15 mL/min/1.73m2) and/or renal or CV death
    - All-cause mortality

    - Комбинирана крайна точка свързана с бъбречната функция : Потвърдено задържане на намаляването с ≥ 40% на eGFR до eGFR < 60 ml/min/1.73 m2 и/или терминален стадий на бъбречна недостатъчност (диализа ≥ 90 дни или бъбречна трансплантация с потвърдено задържане на стойностите на eGFR < 15 ml/min/1.73 m2 ) и/или бъбречна или сърдечно-съдова смърт.
    -Смърт по каквато и да е причина
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For inclusion in the study patients should fulfill the following criteria:
    1. Provision of informed consent prior to any study specific procedures (including run-in)
    2. Female or male aged ≥ 40 years
    3. Diagnosed with T2DM
    4. High Risk for CV event defined as having either established CV disease and/or multiple risk factors:
    - Established CV Disease
    No known cardiovascular disease AND at least two cardiovascular risk factors in addition to T2DM, defined as:
    - Age ≥ 55 years in men and ≥ 60 in women
    AND presence of at least 1 of the following additional risk factors
    - Dyslipidemia
    - Hypertension
    - Current Tobacco use
    1. Подписано информирано съгласие,преди каквито и да било процедури по изпитването (вкл. период на въвеждане)
    2. Жени или мъже ≥ 40 г.
    3. Поставена диагноза Захарен Диабет Тип 2
    4. Висок риск от сърдечно-съдови инциденти, пациентът има или доказана сърдечно-съдова болест и/или множество рискови фактори:
    - Доказана сърдечно-съдова болест
    - ИЛИ
    - Не е известно да има сърдечно-съдова болест И има поне 2 сърдечно-съдови рискови фактора в допълнение към ЗД тип 2, дефинирани като:
    - Възраст ≥ 55 г. за мъжете и ≥ 60 г. за жените
    И наличие на поне един от следните допълнителни рискови фактора
    - Дислипидемия
    - Хипертония
    - Тютюнопушене
    E.4Principal exclusion criteria
    1. Use of the following excluded medications:
    - Current or recent (within 24 months) treatment with pioglitazone and/or use of pioglitazone for a total of 2 years or more during lifetime
    - Current or recent (within 12 months) treatment with rosiglitazone
    - Previous treatment with any SGLT2 inhibitor
    - Any patient currently receiving chronic (>30 consecutive days) treatment with an oral steroid at a dose equivalent to oral prednisolone ≥10 mg (e.g., betamethasone ≥1.2 mg, dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day
    2. Acute cardiovascular event[e.g., acute coronary syndrome (ACS), transient ischemic attack (TIA), stroke, any revascularization, decompensated HF, sustained ventricular tachycardia <8 weeks prior to randomization. Patients with acute cardiovascular events can be enrolled in the run-in period as long as randomization does not occur within 8 weeks of the event.
    3. Systolic BP> 180 or diastolic BP > 100 mmHg at randomization. Patient should be excluded if either the systolic BP is elevated (> 180 mmHg) or the diastolic BP is elevated (> 100 mmHg) on both measurements
    4. Diagnosis of Type 1 diabetes mellitus, MODY, or secondary diabetes mellitus
    5. History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time
    6. History of any other malignancy within 5 years (with the exception of successfully treated non-melanoma skin cancers)
    7. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year)
    8. Any conditions that, in the opinion of the Investigator, may render the patient unable to complete the study including but not limited to cardiovascular (NYHA class IV CHF, recurrent ventricular arrhythmias) or non-cardiovascular disease (e.g., active malignancy with the exception of basal cell carcinoma, cirrhosis, chronic lung disease, severe autoimmune disease) and/or a likely fatal outcome within 5 years
    9. Pregnant or breast-feeding patients

    Patients will be excluded during run-in and should not be randomized if the following are observed from laboratory or observation during enrollment and run-in assessments:
    10. HbA1c ≥12% or HbA1c<6.5% from the central laboratory (nb, the proportion of subjects with an HbA1c between 6.5 % and < 7.0 % will be capped at approximately 5 % of the study)
    11. AST or ALT >3x ULN or Total bilirubin >2.5 x ULN
    12. CrCl < 60 ml/min (based on the Cockroft-Gault equation)
    Употреба на някои от следните медикаменти
    - Настоящо или скорошно (в рамките на 24 месеца) лечение с pioglitazone и/или употреба на pioglitazone в продължение на 2 години или повече когато и да е било.
    - Настоящо или скорошно (в рамките на 12 месеца) лечение с roziglitazone
    - Предишно лечение с SGLT2 инхибитор
    - Пациент, който понастоящем е на хронично (> 30 последователни дни) лечение с пер орален стероид в доза еквивалентна на орален prednisolone ≥ 10 мг. (betamethasone ≥ 1.2 мг. , dexamethasone ≥ 1.5 мг., hydrocortisone ≥ 40 мг., ) дневно.
    2. Остро сърдечно-съдово събитие, напр. остър коронарен синдром (ACS), транзиторна исхемична атака (TIA), инсулт, някаква реваскуларизация, декомпенсирана СН, продължителна тахикардия < от 8 седмици преди рандомизация. Пациенти с остро сърдечно-съдово събитие могат да бъдат включени в периода на въвеждане, само ако рандомизацията няма да бъде направена в рамките на 8 седмици след появата на събитието.
    3. Систолно кръвно налягане > 180 или диастолно кръвно налягане > 100 mmHg измерено на визита „Рандомизация”. Пациентът не трябва да бъде рандомизиран ако систолното кръвно налягане е повишено (> 180 mmHg) или диастолното кръвно налягане е повишено (> 100 mmHg) при двете измервания.
    4. Диагноза ЗД Тип 1, MODY или вторичен ЗД.
    5. Анамнеза за карцином на пикочния мехур или когато и да било проведена лъчева терапия на долната част на корема или тазовата област.
    6. Анамнеза за малигнено заболяване през последните 5 години ( с изключение на успешно лекуван не-меланомен кожен карцином).
    7. Хроничен цистит и/или повтарящи се инфекции на уринарния тракт (3 или повече през последната година).
    8. Състояние, което по преценка на изследователя може да възпрепятства пациента да завърши изпитването, включително сърдечно-съдово заболяване напр. СН NYHA IV, повтаряща се вентрикуларна аритмия или не сърдечно-съдово заболяване напр. активно малигнено заболяване (с изключение на базоцелуларен карцином, цироза, хронично белодробно заболяване, тежка автоимунна болест) и/или очаквана смърт в близките 5 години.
    9. Жени, които са бременни или кърмят.

    Пациентите ще бъдат изключвани от изпитването в периода на въвеждане и не трябва да бъдат рандомизирани, ако по време на включване или в периода на въвеждане се установят следните лабораторни резултати:
    10. HbA1c ≥ 12% или HbA1c < 6.5 % измерен в централна лаборатория ( съотношението на пациенти с HbA1c между 6,5% и <7% ще бъде приблизително 5% от всички пациенти в изпитването)
    11. ASAT или ALAT > 3 х ULN или тоталния билирубин > 2.5 х ULN
    12. CrCL < 60 ml/min ( изчислена по формулата на Cockroft – Gault)
    E.5 End points
    E.5.1Primary end point(s)
    The co-primary outcome variables of the study are the composite endpoint of cardiovascular death, myocardial infarction, or ischemic stroke (time to first event) and the composite endpoint of hospitalization for heart failure or CV death (time to first event). All components of these composites will be adjudicated.
    Ко-първични главни променливи са комбинираната крайна точка от сърдечно-съдова смърт, инфаркт на миокарда или исхемичен инсулт (времето до поява на първо събитие) и комбинираната крайна точка от хоспитализация по повод на сърдечна недостатъчност или сърдечно-съдова смърт (времето до поява на първо събитие). Всички компоненти на тези комбинации ще бъдат оценявани.

    E.5.1.1Timepoint(s) of evaluation of this end point
    This will be evaluated at the pre-specified interim analysis and when the study has been completed.

    Това ще бъде оценявано на предварително определени междинни анализи и когато изпитването завърши.
    E.5.2Secondary end point(s)
    The secondary outcome variables include:
    - Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 ml/min/1.73m2 and/or ESRD (dialysis ≥90 days or kidney transplantation, confirmed sustained eGFR of <15 mL/min/1.73m2) and/or renal or CV death (time to first event)
    - All-cause mortality (time to event)
    Вторичните променливи включват:

    - Комбинирана крайна точка свързана с бъбречната функция : Потвърдено задържане на намаляването с ≥ 40% на стойностите на eGFR до eGFR < 60 ml/min/1.73 m2 (използвайки CKD-EPI формула) и/или терминален стадий на бъбречна недостатъчност (диализа ≥ 90 дни или бъбречна трансплантация, с потвърдено задържане на стойностите на eGFR < 15 ml/min/1.73 m2 ) и/или бъбречна или сърдечно-съдова смърт ( времето до появата на първо събитие)

    - Смърт по каквато и да е причина (времето до поява на първо събитие)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary endpoints will be evaluated when the study has been completed.
    Вторичните крайни точки ще бъдат оценени когато изпитването приключи.
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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.8.4.1Number of sites anticipated in Member State concerned35
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA310
    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
    European Union
    Hong Kong
    Korea, Republic of
    Russian Federation
    South Africa
    United States
    E.8.7Trial 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
    The end of the study is defined as the last visit of the last patient undergoing the study.
    Край на изпитването, според протокола, е дефинирано като: Последна визита на последния пациент, участващ в изпитването.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years6
    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.1.2.1Number of subjects for this age range: 9300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7850
    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 Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state1200
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7600
    F.4.2.2In the whole clinical trial 17150
    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)
    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 Decision2013-07-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-11
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