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    Summary
    EudraCT Number:2015-004825-14
    Sponsor's Protocol Code Number:D1680C00016
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-03-18
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-004825-14
    A.3Full title of the trial
    A 24-Week, Multicenter, Randomized, Double-blind, Parallel Group,
    Placebo-controlled Study to Investigate the Effects of Saxagliptin,
    Saxagliptin Combined with Dapagliflozin, and Sitagliptin in Patients with
    Type 2 Diabetes Mellitus and Heart Failure
    Ensayo de 24 semanas, multicéntrico, aleatorizado, doble ciego con grupos paralelos y controlado con placebo para investigar los efectos de saxagliptina, saxagliptina combinada con dapagliflozina, y sitagliptina en pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A 24-Week study to investigate the effects of saxagliptin,saxagliptin combined with dapagliflozin, sitagliptin and placebo in patients with type 2 diabetes mellitus and heart failure.
    Ensayo de 24 semanas para investigar los efectos de saxagliptina, saxagliptina combinada con dapagliflozina, sitagliptina y placebo en pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca
    A.3.2Name or abbreviated title of the trial where available
    MEASURE-HF
    MEASURE
    A.4.1Sponsor's protocol code numberD1680C00016
    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 Farmacéutica Spain, S.A.
    B.5.2Functional name of contact pointUnidad de Investigación Clínica
    B.5.3 Address:
    B.5.3.1Street AddressC/ Serrano Galvache, 56; Parque Norte, Edificio Álamo
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28033
    B.5.3.4CountrySpain
    B.5.4Telephone number900 200 444
    B.5.6E-mailinformacionEECC-Spain@astrazeneca.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Forxiga
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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 PROPANEDIOL
    D.3.9.1CAS number 960404-48-2
    D.3.9.3Other descriptive nameDAPAGLIFLOZIN PROPANEDIOL MONOHYDRATE
    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.IMP: 2
    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.2.1.1.1Trade name Onglyza
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSaxagliptin
    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 INNSAXAGLIPTIN
    D.3.9.1CAS number 361442-04-8
    D.3.9.3Other descriptive nameSAXAGLIPTIN
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.IMP: 3
    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.2.1.1.1Trade name Onglyza
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSaxagliptin
    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 INNSAXAGLIPTIN
    D.3.9.1CAS number 361442-04-8
    D.3.9.3Other descriptive nameSAXAGLIPTIN
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Januvia
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSitagliptin
    D.3.4Pharmaceutical form Capsule
    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 INNSitagliptin phosphate
    D.3.9.1CAS number 654671-77-9
    D.3.9.3Other descriptive nameSitagliptin phosphate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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.IMP: 5
    D.1.2 and D.1.3IMP RoleComparator
    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.2.1.1.1Trade name Januvia
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameSitagliptin
    D.3.4Pharmaceutical form Capsule
    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 INNSitagliptin phosphate
    D.3.9.1CAS number 654671-77-9
    D.3.9.3Other descriptive nameSitagliptin phosphate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    D.8 Placebo: 2
    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
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    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
    Patients with type 2 diabetes mellitus and heart failure
    Pacientes con diabetes mellitus tipo 2 e insuficiencia cardíaca.
    E.1.1.1Medical condition in easily understood language
    Type 2 diabetes mellitus and heart failure
    Diabetes mellitus tipo 2 e insuficiencia cardíaca
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10011078
    E.1.2Term Coronary artery disease
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To exclude an increase in left ventricular end diastolic volume (LVEDV) index of greater than 10% (non-inferiority margin of 6.5 mL/m2) in patients with T2DM and HFtreated with saxagliptin for 24 weeks,compared to placebo.
    Excluir el aumento del índice de volumen telediastólico ventricular izquierdo (VTDVI) de más del 10 % (margen de ausencia de inferioridad de 6,5 ml/m2) en pacientes con DMT2 e IC tratados con saxagliptina durante 24 semanas, en comparación con placebo.
    E.2.2Secondary objectives of the trial
    - Evaluate the effects of saxagliptin compared to placebo on left ventricular end systolic volume (LVESV) index, left ventricular ejection fraction (LVEF), and left ventricular mass (LVM) after 24 weeks in patients with T2DM and HF

    - Evaluate the effects of saxagliptin compared to placebo on N-terminal prohormone of brain natriuretic peptide (NT-proBNP) after 24 weeks of treatment
    - Evaluar los efectos de saxagliptina en comparación con placebo en el índice de volumen telesistólico ventricular izquierdo (VTSVI), en la fracción de eyección ventricular izquierda (FEVI) y en la masa ventricular izquierda (MVI) después de 24 semanas en pacientes con DMT2 e IC.

    - Evaluar los efectos de saxagliptina en comparación con placebo en la prohormona N-terminal del péptido natriurético cerebral (NT-proBNP) tras 24 semanas de tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of informed consent prior to any study specific procedure (Pre-screening
    ICF and Informed Consent collected at screening)
    2. Male or female, aged > o = 18 years at the time of consent
    3. Documented, controlled T2DM, as defined by:
    -Treatment with stable doses of antidiabetic medications that have not increased or decreased for > o = 8 weeks before screening
    -No planned increases or reductions in antidiabetic medications during the study
    -With central lab HbA1c > o =7.0% and < o = 9.0% value; for patients treated with sulfonylurea agents, central lab HbA1c > o = 7.5% and < o = 9.0% value; during prescreening or screening
    4. HF demonstrated by all 3 of the following criteria:
    -History of HF and LVEF < o = 45% within the last 6 months (echocardiogram, MRI, left ventriculography, or other accepted methodology). Patients without a recent assessment of LV function will undergo a local echocardiogram at the time of screening to determine ejection fraction
    -Elevated NT-proBNP (>900 pg/mL) during screening
    -Stable doses of HF medications (according to local standards of care), that have not increased or decreased (including diuretics, angiotensin converting enzyme [ACE] inhibitors or angiotensin receptor blocking [ARB] agents, beta blockers, and aldosterone antagonists) for > o = 8 weeks prior to screening
    5. Stable HF, with no evidence of volume overload (no rales, jugular venous
    distention, peripheral edema) at screening
    6. Normal sinus rhythm
    7. Body mass index 25 to 40 kg/m2, inclusive
    8. Women of childbearing potential (WOCBP):
    -Must be using appropriate birth control to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of investigational product
    -Must have a negative serum or urine pregnancy test within 72 hours prior to the start of investigational product
    -Must not be breastfeeding
    1. Firma del consentimiento informado antes de que se realice cualquier procedimiento específico del estudio (consentimiento informado de pre-selección y consentimiento informado del estudio en la seleccion).
    2. Hombres o mujeres de > o = 18 años en el momento del consentimiento.
    3. DMT2 controlada y documentada, definida según lo siguiente:
    - Tratamiento con dosis estables de medicamentos antidiabéticos que no hayan aumentado ni disminuido durante > o = 8 semanas anteriores a la selección.
    - Reducciones o aumentos no previstos en la medicación antidiabética durante el estudio.
    - Resultado en Laboratorio Central de HbA1c > o = 7,0 % y < o = 9,0 %; para pacientes tratados con sulfonilureas, resultado en Laboratorio Central de HbA1c > o = 7,5 % y < o = 9,0 %; durante la preselección o la selección.
    4.IC constatada mediante los 3 criterios siguientes:
    - Historial de IC y FEVI < o = 45 % en los últimos 6 meses (ecocardiograma, RM, ventriculografía izquierda u otra metodología aceptada). Los pacientes sin evaluación reciente sobre la función del VI se someterán a un ecocardiograma local en el momento de la selección para determinar la fracción de eyección.
    - NT-proBNP elevado (>900 pg/ml) durante la selección.
    - Dosis estables de medicamentos para IC (según tratamiento de referencia aprobado), que no se hayan aumentado ni reducido (esto incluye diuréticos, inhibidores de la enzima convertidora de la angiotensina [ECA] o agentes bloqueadores del receptor de la angiotensina [BRA], betabloqueantes y antagonistas de la aldosterona) durante > o = 8 semanas anteriores a la selección.
    5. IC estable, sin evidencias de hipervolemia (sin estertores, distensión venosa yugular ni edema periférico) en el momento de la selección.
    6. Ritmo sinusal normal.
    7. Índice de masa corporal de 25 a 40 kg/m2 inclusive.
    8. Mujeres fértiles (MF):
    - Deben emplear métodos anticonceptivos apropiados para evitar elembarazo durante el estudio y durante las 4 semanas posteriores a la administración de la última dosis del producto en investigación (PI).
    - Deben tener una prueba de embarazo negativa en suero o en orina en el plazo de 72 horas antes del inicio de la administración del PI.
    - No deben encontrarse en período de lactancia.
    E.4Principal exclusion criteria
    1. MRI contraindications: all implanted defibrillators; implanted pacemakers and other
    devices/implants that in the judgment of the investigator preclude an MRI evaluation
    2. Atrial fibrillation
    3. Receiving incretin therapy (DPP4 inhibitors, GLP-1 mimetics), or having received incretin therapy within the previous 3 months of screening
    4. Receiving therapy with an SGLT2 inhibitor or having received SGLT2 inhibitor therapy within the previous 3 months of screening
    5. Receiving therapy with a TZD or having received TZD therapy within the previous 3 months of screening
    6. Type 1 diabetes mellitus
    7. History of unstable or rapidly progressing renal disease
    8. History of unexplained microscopic or gross hematuria
    9. Previously documented bladder cancer
    10. Volume depletion as judged by the investigator
    11. A central lab eGFR value <45 mL/min/1.73 m2 on pre-screening or screening
    12. New York Heart Association (NYHA) Class IV HF
    13. Myocardial infarction, stroke, transient ischemic attack, or coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]) within the past 6 months of screening
    14. Inoperable aortic or mitral valvular heart disease. Recent (within 6 months) or planned valvular heart procedure
    15. Heart failure secondary to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, and hypertrophic obstructive cardiomyopathy
    16. Previous cardiac transplantation or transplantation indicated or expected within 6 months of randomization
    17. Contraindications to saxagliptin therapy as outlined in the saxagliptin Investigator?s Brochure, to dapagliflozin therapy as outlined in the dapagliflozin Investigator?s Brochure, or to sitagliptin therapy as outlined in the sitagliptin prescribing information
    18. Current treatment with strong cytochrome P450 (CYP) 3A4/5 inhibitors
    19. Involvement in the planning and/or conduct of the study (applies to both AZ staff and/or staff at the study site)
    20. Previous enrollment or randomization in the present study
    21. Participation in another clinical study with an investigational product during the last 30 days
    22. Patients either employed by or immediate relatives of the Sponsor
    23. Known human immunodeficiency virus (HIV) infection
    24. Severe hepatic disease, including chronic active hepatitis. Positive serologic evidence of current infectious liver disease, including patients who are known to be positive for hepatitis B viral antibody IgM, hepatitis B surface antigen, or hepatitis C virus antibody; or aspartate transaminase (AST) or alanine transaminase (ALT)>3X the upper limit of normal; or total bilirubin (TB) >2 mg/dL
    25. History of diabetic ketoacidosis (DKA) requiring medical intervention (eg, emergency room visit and/or hospitalization) within 1 month prior to the Screening visit
    26. History of malignancy within the last 5 years, excluding successful treatment of basal or squamous cell skin cancer
    27. Patients who, in the judgement of the investigator, may be at risk for dehydration
    28. Pregnant, positive pregnancy test, planning to become pregnant during clinical trial or breast feeding
    29. History of any clinically significant disease or disorder which, in the opinion of the investigator, may put the patient at risk because of participation in the study, may influence the results, or may limit the patient's ability to participate in or complete the study
    30. Unable or unwilling to provide written informed consent
    1. Contraindicaciones de la RM: cualquier desfibrilador implantado; marcapasos implantados y otros dispositivos/implantes que, según el criterio del investigador, impidan una evaluación mediante RM.
    2. Fibrilación auricular.
    3. Recibir tratamiento con incretinas (inhibidores de DPP4, miméticos de GLP-1) o haber recibido tratamiento con incretinas en los 3 meses previos a la selección.
    4. Recibir tratamiento con un inhibidor de SGLT2 o haber recibido tratamiento con un inhibidor de SGLT2 en los 3 meses previos a la selección.
    5. Recibir tratamiento con un inhibidor de TZD o haber recibido tratamiento con un inhibidor de TZD en los 3 meses previos a la selección.
    6. Diabetes mellitus tipo 1.
    7. Antecedentes de enfermedad renal inestable o de progreso rápido.
    8. Antecedentes de hematuria microscópica o macroscópica sin causa aparente.
    9. Cáncer de vejiga documentado previamente.
    10. Hipovolemia a criterio del investigador.
    11. Resultado en Laboratorio Central de eGFR <45 ml/min/1,73 m2 en el período de preselección o selección.
    12. IC de clase IV según la Asociación de cardiología de Nueva York (NYHA).
    13. Infarto de miocardio, accidente cerebrovascular, accidente isquémico transitorio o revascularización coronaria (intervención coronaria percutánea [ICP] o cirugía de derivación coronaria con injerto [CDCI]) en los 6 meses previos a la selección.
    14. Valvulopatía aórtica o valvulopatía mitral no operables. Intervención quirúrgica por valvulopatía reciente (últimos 6 meses) o prevista.
    15. IC secundaria a miocardiopatía restrictiva, miocarditis activa, pericarditis constrictiva o miocardiopatía obstructiva hipertrófica.
    16. Trasplante cardíaco previo o trasplante indicado o previsto en un período de 6 meses tras la aleatorización
    17. Contraindicaciones relacionadas con el tratamiento con saxagliptina tal como se describe en el manual del investigador (MI) de saxagliptina, con el tratamiento con dapagliflozina tal como se describe en el MI de dapagliflozina o con el tratamiento con sitagliptina tal como se describe en la información de prescripción de sitagliptina.
    18. Tratamiento actual con inhibidores potentes del citocromo P450 (CYP) 3A4/5.
    19. Implicación en la planificación o la realización del estudio (se aplica al personal de AZ o al personal del centro del estudio).
    20. Inclusión o aleatorización previas en el estudio actual.
    21. Participación en otro estudio clínico con un PI en los últimos 30 días.
    22. Pacientes que trabajan para el promotor o que sean familiares directos.
    23. Infección por el virus de la inmunodeficiencia humana (VIH) conocida.
    24. Enfermedad hepática grave, incluida la hepatitis activa crónica. Evidencia serológica positiva de enfermedad hepática infecciosa actual, incluidos pacientes con un resultado positivo conocido de anticuerpos IgM contra el virus de la hepatitis B, antígeno de superficie del virus de la hepatitis B o anticuerpo del virus de la hepatitis C; o asparato transaminasa (AST) o alanina aminotransferasa (ALT) >3 x el límite superior de la normalidad; o bilirrubina total (BT) >2 mg/dl.
    25. Antecedentes de cetoacidosis diabética (CAD) que haya requerido intervención médica (p. ej., visita a un centro de urgencias u hospitalización) en el mes previo a la visita de selección.
    26. Antecedentes de neoplasia maligna en los últimos 5 años, excepto tratamiento con respuesta eficaz de carcinoma basocelular o epidermoide.
    27. Pacientes que, según el criterio del investigador, pueden estar en riesgo de sufrir deshidratación.
    28. Pacientes embarazadas, con prueba de embarazo positiva o que tengan previsto quedarse embarazadas durante el ensayo clínico o que se encuentren en período de lactancia.
    29. Antecedentes de cualquier enfermedad o trastorno de importancia clínica que, según la opinión del investigador, pueda poner en riesgo al paciente debido a su participación en el estudio, pueda afectar a los resultados o limitar la capacidad del paciente para participar o finalizar el estudio.
    30. Pacientes que no pueden o que se niegan a otorgar su consentimiento informado por escrito.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in LVEDV index measured by Magnetic Resonance Imaging (MRI)
    Cambio con respecto al valor inicial del índice VTDVI medido mediante resonancia magnética (RM)
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 semanas
    E.5.2Secondary end point(s)
    -Change from baseline in LVESV index, LVEF, and LVM measured by MRI
    - Change from baseline in NT-proBNP
    - Cambio con respecto al valor inicial en el índice VTSVI, FEVI y MVI medidos mediante RM.

    - Cambio con respecto al valor inicial en NT-proBNP.
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks
    24 semanas
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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) 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) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Canada
    Chile
    Hungary
    Korea, Republic of
    Russian Federation
    Spain
    Taiwan
    Thailand
    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
    Last Subject Last Visit (LSLV)
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days18
    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: 375
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 65
    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 state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 440
    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)
    Standard of care
    Cuidados standar.
    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 Decision2016-05-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-02
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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