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    Summary
    EudraCT Number:2020-004101-32
    Sponsor's Protocol Code Number:D4325C00001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Restarted
    Date on which this record was first entered in the EudraCT database:2021-07-08
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2020-004101-32
    A.3Full title of the trial
    A Phase 2b Multicentre, Randomised, Double-Blind, PlaceboControlled, Parallel Group Dose-Ranging Study to Assess the Efficacy, Safety and Tolerability of Zibotentan and Dapagliflozin
    in Patients with Chronic Kidney Disease with Estimated Glomerular Filtration Rate (eGFR) Between 20 and 60 mL/min/1.73 m2
    Estudio en fase IIb, multicéntrico, aleatorizado, doble ciego, controlado con placebo, de grupos paralelos y de medición de dosis para evaluar la eficacia, seguridad y tolerabilidad de zibotentán y dapagliflozina en pacientes con enfermedad renal crónica con una tasa de filtración glomerular estimada (TFGe) entre 20 y 60 ml/min/1,73 m2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Zibotentan and Dapagliflozin for the Treatment of Chronic Kidney Disease (ZENITH-CKD trial)
    Zibotentán y dapagliflozina para el tratamiento de la ERC (ensayo ZENITH-CKD)
    A.3.2Name or abbreviated title of the trial where available
    Zenith-CKD
    ZENITH-CKD
    A.4.1Sponsor's protocol code numberD4325C00001
    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
    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 AB
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street Addressnot applicable
    B.5.3.2Town/ citynot applicable
    B.5.3.3Post codenot applicable
    B.5.3.4CountryUnited States
    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 nameZibotentan capsule
    D.3.4Pharmaceutical form Capsule, hard
    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 INNZibotentan
    D.3.9.1CAS number 186497-07-4
    D.3.9.3Other descriptive nameZIBOTENTAN
    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: 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 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 nameZibotentan capsule
    D.3.4Pharmaceutical form Capsule, hard
    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 INNZibotentan
    D.3.9.1CAS number 186497-07-4
    D.3.9.3Other descriptive nameZIBOTENTAN
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.5
    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: 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 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 nameZibotentan capsule
    D.3.4Pharmaceutical form Capsule, hard
    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 INNZibotentan
    D.3.9.1CAS number 186497-07-4
    D.3.9.3Other descriptive nameZIBOTENTAN
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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 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 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.3.9.2Current sponsor codeBMS-512148-05
    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 placeboCapsule, hard
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Chronic Kidney Disease
    Enfermedad renal crónica
    E.1.1.1Medical condition in easily understood language
    Chronic Kidney Disease
    Enfermedad renal crónica
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10064848
    E.1.2Term Chronic kidney disease
    E.1.2System Organ Class 10038359 - Renal and urinary 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 evaluate the effect of zibotentan and dapagliflozin in combination and alone versus placebo on UACR.
    Evaluar el efecto de zibotentán y dapagliflozina en combinación y en monoterapia frente a placebo en el cociente albúmina/creatinina en orina (CACO).
    E.2.2Secondary objectives of the trial
    1. To determine the change in UACR for doses of zibotentan combined ith 10 mg dapagliflozin versus 10 mg dapagliflozin alone.

    2. To determine the change in office systolic and diastolic BP for doses of zibotentan combined with 10 mg dapagliflozin and for zibotentan and 10 mg dapagliflozin alone versus placebo.

    3. To characterise the dose-response relationship (relationship between different doses of zibotentan/a fixed dose of dapagliflozin and UACR reduction).

    4. To determine the effect of ranging doses of zibotentan and dapagliflozin in combination and alone on eGFR.
    1.Determinar el cambio del CACO en las dosis de zibotentán combinado con 10 mg de dapagliflozina frente a 10 mg de dapagliflozina en monoterapia.

    2. Determinar el cambio en la PA sistólica y diastólica en la consulta para las dosis de zibotentán combinado con 10 mg de dapagliflozina y para zibotentán y 10 mg de dapagliflozina en monoterapia frente a placebo.

    3. Caracterizar la relación dosis-respuesta (relación entre diferentes dosis de zibotentán/una dosis fija de dapagliflozina y reducción del CACO).

    4.Determinar el efecto de los intervalos de las dosis de zibotentán y dapagliflozina en combinación y en monoterapia en la TFGe.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Type of Participant and Disease Characteristics / Laboratory Parameters
    1. Diagnosis of CKD, defined as:
    (a) Part A: eGFR (CKD-EPI) ≥ 30 and ≤ 60 mL/min/1.73 m2
    Part B, if safety data from Part A allow (otherwise same as in Part A):
    eGFR
    (CKD-EPI) ≥ 20 and ≤ 60 mL/min/1.73 m2

    2. Urine albumin to creatinine ratio (UACR) ≥ 200 and ≤ 5000 mg albumin/g creatinine, based on a single first morning void spot urine sample at screening

    Medical Treatment
    3 No current or prior (within 1 month of screening) medical treatment with an SGLT2i or any FDC with SGLT2i (such as SGLT2i + metformin).

    4 On a stable dose of ACEi and/or ARB (≥ 4 weeks before screening).

    5 No current or prior treatment within 3 months prior to screening with cytotoxic therapy, immunosuppressive therapy or other immunotherapy.

    Weight
    6 Body mass index (BMI) ≤ 40 kg/m2 .

    Sex
    7 Male or female of non-childbearing potential.

    Reproduction
    8 Female participants must have a negative pregnancy test at screening, must not be lactating, and must be of non-childbearing potential, confirmed at screening by fulfilling one of the following criteria:
    (a) Postmenopausal defined as amenorrhoea for at least 12 months or more following cessation of all exogenous hormonal treatments and FSH and LH levels in the postmenopausal range.

    (b) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.

    9 Male participants must be surgically sterile, abstinent, or in conjunction with a female sexual partner, using a highly effective method of contraception for the duration of the study (from the time they sign consent) and for 3 months after the last dose of investigational product to prevent any pregnancies. Male study participants must not donate or bank sperm during this same time period.
    Tipo de participante y características patológicas/parámetros analíticos
    1. Diagnóstico de nefropatía crónica (Chronic Kidney Disease, CKD, definida como:
    Parte A: eGFR [CKD-EPI]) >= 30 y <= 60 ml/min/1,73 m2
    Parte B, si los datos de seguridad de la Parte A lo permiten (si no, igual que en la Parte A): eGFR (CKD-EPI) >= 20 y <= 60 ml/min/1,73

    2. Cociente albúmina/creatinina en orina (UACR) >= 200 y <= 5000 mg de albúmina/g de creatinina, basado en una única muestra puntual de orina de la primera micción matutina en el momento de la selección.

    Tratamiento médico
    3. Sin tratamiento médico activo ni anterior (en el mes anterior a la selección) con un SGLT2i o con cualquier FDC con SGLT2i (como SGLT2i + metformina).

    4. Con una dosis estable de ACEi y/o ARB (>= 4 semanas antes de la selección).

    5. Sin tratamiento citotóxico, inmunodepresor u otra inmunoterapia activa ni anterior en los 3 meses anteriores a la selección.

    Peso corporal
    6. Índice de masa corporal (Body mass index, BMI) <= 40 kg/m2.

    Sexo
    7. Varón o mujer sin posibilidad de quedarse embarazada.

    Reproducción
    8. Las mujeres participantes deben presentar una prueba de embarazo negativa en el momento de la selección, no deben estar en período de lactancia y no deben tener posibilidad de quedarse embarazadas, confirmada en el momento de la selección mediante el cumplimiento de uno de los siguientes criterios:
    (a) Posmenopáusicas, definidas como amenorreicas durante al menos 12 meses o más después de la interrupción de todos los tratamientos hormonales exógenos y niveles de FSH y LH en el intervalo posmenopáusico.
    (b) Documentación de esterilización quirúrgica irreversible por histerectomía, ooforectomía bilateral o salpingectomía bilateral, pero no por ligadura de trompas.

    9. Los varones participantes deben ser quirúrgicamente estériles, abstinentes o bien, conjuntamente con una pareja sexual femenina, utilizar un método anticonceptivo altamente eficaz durante el estudio (desde el momento en que firmen el consentimiento) y hasta 3 meses después de la última dosis del producto experimental para impedir cualquier embarazo. Los varones participantes en el estudio no deben donar ni conservar semen durante este mismo período.
    E.4Principal exclusion criteria
    Medical Conditions
    1 Minimal change disease, unstable rapidly progressing renal disease, and/or renal disease requiring significant immunosuppression, autosomal dominant or autosomal recessive polycystic kidney disease, or anatomical causes of CKD.

    2 History of epilepsy syndrome.

    3 Participants with NYHA functional HF class III or IV.

    4 Acute coronary syndrome (ACS) events within 3 months prior to screening.

    5 Participants with a confirmed BNP ≥ 200 pg/mL or BNP ≥ 400 pg/mL if with atrial fibrillation.

    6 Participants with unstable HF requiring hospitalisation for optimization of HF treatment and/or who have not been stable on HF therapy within 6 months prior to screening.

    7 Heart failure due to cardiomyopathies that would primarily require specific other treatment: eg, cardiomyopathy due to pericardial disease, amyloidosis or other infiltrative diseases, cardiomyopathy related to congenital heart disease, primary hypertrophic cardiomyopathy,
    cardiomyopathy related to toxic or infective conditions (ie, chemotherapy, infective myocarditis, septic cardiomyopathy).

    8 High output HF (eg, due to hyperthyroidism or Paget's disease).

    9 Heart failure due to primary cardiac valvular disease/dysfunction, severe functional mitral or tricuspid valve insufficiency, or planned cardiac valve repair/replacement.

    10 Participants with uncontrolled diabetes mellitus (HbA1c > 12%).

    11 Participants with T1DM.

    12 Hyponatremia, defined as serum Na+ < 135 mmol/L at the time of randomisation.

    13 Intermittent or persistent second or third degree atrioventricular(AV) block after sinus node dysfunction, with clinically significant bradycardia or sinus pause when not treated with pacemaker.

    14 Prolonged QT interval (QTcF > 470ms) on ECG at randomisation visit (Visit 2), known congenital long QT syndrome or history of QTprolongation associated with other medications.

    15 History of any life-threatening cardiac dysrhythmia (continuous or paroxysmal or uncontrolled ventricular rate in participants with atrial fibrillation or atrial flutter).

    16 Cardiac surgery or non-elective percutaneous coronary interventions (PCI/TAVI) (within
    3 months) or open chest coronary artery bypass grafting or valvular repair/replacement (within 12 months) prior to screening or is planned to undergo any of these procedures after randomisation.

    17 Heart transplantation or left ventricular assist device at any time.

    18 Kidney or any organ transplantation.

    19 History or ongoing allergy/hypersensitivity, as judged by theinvestigator, to SGLT2i (eg, dapagliflozin, canagliflozin, empagliflozin) or drugs with a similar chemical structure to zibotentan.

    20 Any clinically significant disease or disorder (eg, cardiovascular, gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, psychiatric, major physical impairment) which, as judged by the investigator, might put the participant at risk because of participation in the study, or probable alternative primary reason for participant's symptoms in judgment of investigator, including but not limited to:
    (a) Isolated pulmonary arterial hypertension (defined as mean PAP ≥ 25 mmHg at rest)
    or right ventricular failure; in the absence of left-sided HF.

    (b) Anaemia defined as haemoglobin (Hb) level < 100 g/L or 10 g/dL at randomization visit (Visit 2).
    (c) Severe chronic obstructive pulmonary disease (COPD) or other lung disease including but not limited to pulmonary fibrosis requiring chronic O2therapy, regular nebuliser use, or oral steroid therapy.

    21 Chronic cystitis and/or recurrent urinary tract infections (3 or more in the previous year).

    22 Stroke, transient ischemic attack, carotid surgery, or carotid angioplasty within previous 3 months prior to screening.

    23 Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas
    of the skin) and malignancies 5 years prior to screening.

    24 Severe hepatic impairment (Child-Pugh class C Hepatic impairment), aspartate transaminase [AST] or alanine transaminase [ALT] > 2x the upper limit of normal [ULN]; or total bilirubin > 2x ULN at time of screening. An isolated increase in bilirubin in participants with known Gilbert's syndrome is not a reason for exclusion.

    25 Participants with newly detected pathological laboratory values or an ongoing disease condition requiring investigation and/or initiation or adjustment of current treatment (in the opinion of the investigator).

    26 Drug or alcohol abuse, either current or within 12 months before screening.

    27 Positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody, at screening.
    Enfermedades
    1. Nefropatía de cambios mínimos, nefropatía inestable de progresión rápida o nefropatía que requiere una inmunodepresión considerable, poliquistosis renal autosómica dominante o recesiva, o causas anatómicas de CKD.

    2. Antecedentes de síndrome epiléptico.

    3. Participantes con IC de clase funcional III o IV de la NYHA.

    4. Episodios de síndrome coronario agudo en los 3 meses anteriores a la selección.

    5. Participantes con un NBP confirmado >= 200 pg/ml o NBP 400 pg/ml si tienen fibrilación auricular.

    6. Participantes con IC inestable que necesitan hospitalización para la optimización del tratamiento de la IC o que no han mantenido la estabilidad bajo tratamiento de la IC en los 6 meses anteriores a la selección.

    7. Insuficiencia cardíaca debida a miocardiopatías que requerirían principalmente otro tratamiento específico.

    8. IC de alto gasto (p. ej., por hipertiroidismo o enfermedad de Paget).

    9. Insuficiencia cardíaca debida a valvulopatía/disfunción valvular cardíaca primaria, insuficiencia funcional valvular mitral o tricuspídea grave o reparación/sustitución valvular cardíaca programada.

    10. Participantes con diabetes mellitus no controlada (HbA1c > 12 %).

    11. Participantes con DM1.

    12. Hiponatremia, definida como Na+ sérico <135 mmol/l en el momento de la aleatorización.

    13. Bloqueo auriculoventricular (AV) intermitente o persistente de segundo o tercer grado tras disfunción del nodo sinusal, con bradicardia clínicamente significativa o pausa sinusal, no tratados con marcapasos.

    14. Intervalo QT prolongado (QTcF > 470 ms) en el ECG de la visita de aleatorización (visita 2), síndrome de QT largo congénito conocido o antecedentes de prolongación del QT asociada con otros medicamentos.

    15. Antecedentes de cualquier arritmia cardíaca potencialmente mortal (frecuencia ventricular continua o paroxística o no controlada en participantes con fibrilación auricular o aleteo[flutter] auricular).

    16. Intervención quirúrgica cardíaca o angioplastia coronaria transluminal percutánea no programadas (PCI/TAVI) (en el plazo de 3 meses) o revascularización coronaria o reparación/sustitución valvular a corazón abierto (en el plazo de 12 meses) antes de la selección o previsión de someterse a cualquiera de estas intervenciones después de la aleatorización.

    17. Trasplante cardíaco o dispositivo de asistencia ventricular izquierda en cualquier momento.

    18. Trasplante renal o de cualquier órgano.

    19. Alergia/hipersensibilidad activa o antecedentes de la misma, a criterio del investigador, a los SGLT2i o fármacos con una estructura química similar a la del zibotentán.

    20. Cualquier enfermedad o trastorno clínicamente significativo que, a criterio del investigador, podría poner en riesgo al participante por su participación en el estudio, o probable razón principal alternativa de los síntomas del participante, a juicio del investigador, incluso, entre otras:
    (a) Hipertensión arterial pulmonar aislada (definida como PAP media >= 25 mmHg en reposo) o insuficiencia ventricular derecha; en ausencia de IC izquierda.
    (b) Anemia, definida como un nivel de hemoglobina (Hb) <100 g/l o 10 g/dl en la visita de aleatorización (visita 2).
    (c) Enfermedad pulmonar obstructiva crónica (EPOC) grave u otra neumopatía, incluso, entre otras, fibrosis pulmonar que requiera tratamiento crónico con O2, uso habitual de nebulizadores o tratamiento con esteroides orales.

    21. Cistitis crónica o infecciones recurrentes de las vías urinarias. (3 o más en el año anterior).

    22. Ictus, accidente isquémico transitorio, intervención quirúrgica carotídea o angioplastia carotídea en los 3 meses anteriores a la selección.

    23. Neoplasia maligna activo que requiera tratamiento (excepto los carcinomas basocelulares o espinocelulares cutáneos) o presentada en los 5 años anteriores a la selección.

    24. Insuficiencia hepática grave, aspartato··transaminasa (AST) o alanina··transaminasa (ALT) >2x el límite superior de la normalidad ; o bilirrubina total >2x ULN en el momento de la selección. Un aumento aislado de la bilirrubina en participantes con síndrome de Gilbert conocido no es causa de exclusión.

    25. Participantes con valores analíticos patológicos recién detectados o enfermedad en curso que requiera investigación o inicio o ajuste del tratamiento actual (a criterio del investigador).

    26. Drogadicción o alcoholismo, ya sea activo o en los 12 meses anteriores a la selección.

    27. Positividad de anticuerpos contra la hepatitis C, antígeno de superficie del virus de la hepatitis B o anticuerpo contra la nucleocápside (core) del virus de la hepatitis B, en la fase de selección.
    E.5 End points
    E.5.1Primary end point(s)
    Change in log-transformed UACR from baseline to Week 12.
    Cambio en el CACO transformado logarítmicamente desde el inicio hasta la semana 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 12
    Semana 12
    E.5.2Secondary end point(s)
    1. Change in log-transformed UACR from baseline to Week 12.

    2. Change in BP from baseline (Visit 2) to Week 12

    3. The least squares mean change of UACR at Week 12 from the 3
    Zibo/Dapa dose groups and the dapagliflozin monotherapy group.

    4. Change in eGFR from baseline to Week 1.
    -Change in eGFR from baseline to Week 12.
    -Change in eGFR from baseline to Week 14.
    -Change in eGFR from Week 1 to Week 12.
    1. Cambio en el CACO transformado logarítmicamente desde el inicio hasta la semana 12.

    2. Variación en la PA desde el inicio (visita 2) hasta la semana 12.

    3. El cambio medio de mínimos cuadrados del CACO en la semana 12 de los 3 grupos de dosis de zibo/dapa y el grupo de dapagliflozina en monoterapia.

    4.
    - Cambio en la TFGe desde el inicio hasta la semana 1.
    - Cambio en la TFGe desde el inicio hasta la semana 12.
    - Cambio en la TFGe desde el inicio hasta la semana 14.
    - Cambio en la TFGe desde la semana 1 hasta la semana 12.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. week 12

    2. week 12

    3. week 12

    4.
    week 1
    week 12
    week 14
    week 12
    1. Semana 12

    2. Semana 12

    3. Semana 12

    4.
    Semana 1
    Semana 12
    Semana 14
    Semana 12
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 trial10
    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 concerned13
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA69
    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
    Australia
    Bosnia and Herzegovina
    Brazil
    Canada
    Georgia
    Japan
    Korea, Republic of
    Malaysia
    Serbia
    South Africa
    Taiwan
    Ukraine
    United States
    Belgium
    Bulgaria
    Denmark
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    United Kingdom
    Argentina
    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
    LPLV
    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 months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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: 330
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 330
    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 state67
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 189
    F.4.2.2In the whole clinical trial 660
    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)
    none
    Ninguno
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-07-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-03
    P. End of Trial
    P.End of Trial StatusRestarted
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