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    Summary
    EudraCT Number:2021-003062-12
    Sponsor's Protocol Code Number:PA-ADPKD-301
    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:2021-10-20
    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 number2021-003062-12
    A.3Full title of the trial
    A Phase 3 Study of the Efficacy and Safety of Lixivaptan in Participants with Autosomal Dominant Polycystic Kidney Disease Consisting of a 1-year Double-blind, Placebo-controlled, Randomized Phase and a 1-year Open-Label Phase: The ACTION Study.
    Estudio de fase III para evaluar la eficacia y la seguridad de lixivaptán en participantes con enfermedad renal poliquística autosómica dominante con una fase aleatorizada, controlada con placebo y doble ciego de 1 año y una fase abierta de 1 año: el estudio ACTION
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to look at how safe and how effective Lixivaptan is in patients with kidney disease compared to a placebo treatment.
    Ensayo clínico para comprobar la seguridad y eficacia de Lixivaptan en pacientes con enfermedad renal en comparación con placebo.
    A.3.2Name or abbreviated title of the trial where available
    ACTION
    A.4.1Sponsor's protocol code numberPA-ADPKD-301
    A.5.4Other Identifiers
    Name:INDNumber:136,419
    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 SponsorPalladio Biosciences Inc.,
    B.1.3.4CountryUnited States
    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 supportPalladio Biosciences Inc.,
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPalladio Biosciences Inc.,
    B.5.2Functional name of contact pointMilena Kanova
    B.5.3 Address:
    B.5.3.1Street Address5 Walnut Grove Drive, Suite 120
    B.5.3.2Town/ cityHorsham
    B.5.3.3Post codePA 19044
    B.5.3.4CountryUnited States
    B.5.4Telephone number447780430583
    B.5.6E-mailmkanova@palladiobio.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 nameLixivaptan
    D.3.2Product code 0C23
    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 INNLixivaptan
    D.3.9.1CAS number 168079-32-1
    D.3.9.2Current sponsor code0C23
    D.3.9.3Other descriptive nameLixivaptan
    D.3.9.4EV Substance CodeSUB32850
    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.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
    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
    Autosomal Dominant Polycystic Kidney Disease
    Enfermedad renal poliquística autosómica dominante (ERPAD)
    E.1.1.1Medical condition in easily understood language
    Kidney disorder characterized by cyst formation and progressive enlargement in the kidney, liver, and other organs
    Trastorno renal caracterizado por la formación de quistes y agrandamiento progresivo en el riñón, el hígado y otros órganos.
    E.1.1.2Therapeutic area Body processes [G] - Genetic Phenomena [G05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objective of Part 1:
    •To demonstrate the efficacy of lixivaptan compared to placebo in the slowing of deterioration in kidney function in participants with ADPKD as demonstrated by the annualized change from baseline in estimated glomerular filtration rate (eGFR).
    The key safety objective of Part 1:
    •To compare the incidences of liver chemistry test elevations in participants randomized to lixivaptan with participants randomized to placebo.

    Primary Objective of Part 2:
    •To demonstrate the continued efficacy of lixivaptan in the slowing of deterioration in kidney function in participants randomized to lixivaptan in the double-blind phase (Part 1) as measured by the annualized change from baseline (Part 2) in eGFR at the end of the open-label phase (Part 2).
    The key safety objective of Part 2:
    •To assess the incidence of liver chemistry test abnormalities during the open-label phase.
    Parte 1 (año 1):
    El objetivo principal de la eficacia:
    • Demostrar la eficacia de lixivaptan en comparación con el placebo en la
    ralentización del deterioro de la función renal en participantes con
    ERPAD, según lo demostrado por el cambio anualizado desde el inicio en
    la tasa de filtración glomerular estimada (TFGe).
    El objetivo clave de la seguridad:
    • Comparar las incidencias de aumentos en las pruebas de bioquímica hepática en participantes aleatorizados a lixivaptan con las de los
    participantes aleatorizados al placebo.
    El objetivo clave s:
    • Demostrar la eficacia continuada de lixivaptan en la ralentización del
    deterioro de la función renal en participantes aleatorizados a lixivaptan
    en la fase doble ciego (parte 1), según lo medido por el cambio
    anualizado desde el inicio (parte 2) en la TFGe al final de la fase abierta
    (parte 2).
    El objetivo clave de la seguridads:
    • Evaluar la incidencia de anomalías en las pruebas de bioquímica hepática durante la fase abierta.
    E.2.2Secondary objectives of the trial
    The secondary objectives of Part 1:
    •To compare the rate of change (slope) in on-treatment eGFR in participants treated with lixivaptan to participants treated with placebo.
    •To assess the effect of lixivaptan on total kidney volume (TKV) as measured by magnetic resonance imaging (MRI) compared to placebo.
    The secondary safety objective of Part 1:
    •To assess the non-hepatic safety and tolerability of lixivaptan.
    The secondary objectives of Part 2 are:
    •To assess the rate of change (slope) in on-treatment eGFR in Part 2 in participants treated with lixivaptan in Part 1 and Part 2;
    •To assess the effect of lixivaptan on TKV as measured by MRI in Part 2 in participants treated
    with lixivaptan in Part 1 and Part 2.
    The secondary safety objective of Part 2:
    •To assess the non-hepatic safety and tolerability of lixivaptan.
    Los objetivos secundarios de la eficacia de la parte 1 son:
    • Comparar la tasa de cambio (pendiente) en la TFGe durante el
    tratamiento en participantes tratados con lixivaptan con la de los
    participantes tratados con el placebo.
    • Evaluar el efecto de lixivaptan en el volumen renal total (VRT), según
    lo medido mediante resonancia magnética (RM), en comparación con el placebo.
    El objetivo secundario de la seguridad de la parte 1:
    • Evaluar la seguridad no hepática y la tolerabilidad de lixivaptan.
    Los objetivos secundarios de la parte 2:
    • Evaluar la tasa de cambio (pendiente) en la TFGe durante el tratamiento en la parte 2 en participantes tratados con lixivaptan en la parte 1 y en la parte 2.
    • Evaluar el efecto de lixivaptan en el VRT, según lo medido mediante RM, en la parte 2 en participantes tratados con lixivaptan en la parte 1 y en la parte 2.
    El objetivo secundario de la seguridad de la parte 2 es:
    Evaluar la seguridad no hepática y la tolerabilidad de lixivaptan.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Male or female, between 18 and 60 years of age (inclusive) at the time of Screening (Visit 1a).
    2.Diagnosis of ADPKD by modified Pei criteria:
    •For participants with family history of ADPKD, by ultrasound:
    - 18-39 years: ≥3 cysts, unilateral or bilateral;
    - 40-59 years: ≥2 cysts in each kidney;
    - 60 years: ≥4 cysts in each kidney; or
    •For participants with family history of ADPKD, by computerized tomography (CT) or MRI:
    - 18-40 years: ≥10 cysts in both kidneys; or
    •For participants without family history of ADPKD
    - a minimum of 10 cysts per kidney by any radiologic method and
    exclusion of other cystic kidney diseases (multiple simple kidney
    cysts, renal tubular acidosis, cystic dysplasia of the kidney,
    multicystic kidney, multilocular cysts of the kidney, medullary
    cystic kidney and acquired cystic disease of the kidney); or
    - genetic diagnosis of ADPKD.
    3.Mayo Clinic ADPKD classification of 1C, 1D, or 1E based on age and height-adjusted total kidney volume as determined by kidney MRI obtained during Screening, as assessed by the central imaging vendor.
    4.eGFR ≥25 mL/min/1.73 m2 and ≤90 mL/min/1.73 m2 based on the mean of 2 eGFR determinations (Visits 1a and 2 or Visits 1b and 2, if Visit 1b is required) calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation
    from serum creatinine values obtained during Screening (Appendix 1 (Section 13.1)) Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a or Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visits 1a and 2 or Visits 1b and 2 are available.
    5.Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the participant) as suggested by the Kidney Disease Improving Global Outcomes (KDIGO) “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease,” without the use of a diuretic.
    6.Body mass index (BMI) between 18 and 40 kg/m2 (inclusive) at the time of Screening.
    7.Female participants must:
    a. not be pregnant, lactating, or breastfeeding.
    b. be either postmenopausal (defined as amenorrhea for ≥ 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy) or, if of child-bearing potential (WOCBP), agree to practice acceptable methods of birth control or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug. Birth control methods that can be used during the study include the following:
    • hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, transdermal) progestogen-only hormonal contraception (i.e., oral, injectable, implantable)
    • intrauterine device (IUD), including progestin-containing intrauterine devices
    • intrauterine hormone-releasing system (IUS)
    • male sexual partner who has been vasectomized for at least 3 months prior to Screening and who has obtained a follow-up negative sperm count and is the sole sexual partner
    • bilateral tubal ligation
    • Essure® procedure (tubal occlusion)
    • male or female condom with spermicide (cream, spray, gel, suppository, or polymer film)
    • diaphragm, cervical cap, or contraceptive sponge with spermicide (with or without male condom)
    8.Male participants must agree to use an acceptable form of birth control (see list above) or remain abstinent (only if this is the usual and preferred lifestyle of the participant) during the full duration of the trial and for 30 days after the last dose of study drug.
    9.Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study-related procedures.
    selección (visita 1a).
    2. Diagnóstico de ERPAD mediante los criterios de Pei modificados.
    3. En participantes con antecedentes familiares de ERPAD, mediante
    ecografía:
    • 18-39 años: ≥3 quistes, unilaterales o bilaterales.
    • 40-59 años: ≥2 quistes en cada riñón.
    • 60 años: ≥4 quistes en cada riñón. O
    • En participantes con antecedentes familiares de ERPAD, mediante
    tomografía axial computarizada (TAC) o RM:
    • 18-40 años: ≥10 quistes en ambos riñones. O
    • En participantes sin antecedentes familiares de ERPAD:
    • un mínimo de 10 quistes por riñón mediante cualquier método
    radiográfico y exclusión de otras enfermedades renales quísticas (varios
    quistes renales simples, acidosis tubular renal, displasia renal quística,
    riñón multiquístico, quistes renales multiloculares, riñón quístico
    medular y enfermedad renal quística adquirida). O
    • diagnóstico genético de ERPAD.
    4. Clasificación de la ERPAD de Mayo Clinic de 1C, 1D o 1E con base en el
    volumen renal total ajustado por estatura y edad según lo determinado
    por la RM renal obtenida durante la selección, según lo evaluado por el
    proveedor de obtención de imágenes central.
    5. TFGe ≥25 ml/min/1,73 m2 y ≤90 ml/min/1,73 m2 con base en la
    media de 2 determinaciones de TFGe (visitas 1a y 2 o visitas 1b y 2, si se
    requiere la visita 1b) calculada mediante la ecuación de la Chronic
    Kidney Disease Epidemiology Collaboration (CKD-EPI) con los valores de
    creatinina sérica obtenidos durante la selección. Nota: Este criterio se
    revisará de forma preliminar en la visita 2 con base en los resultados de
    la visita 1a o visita 1b (si se requiere la visita 1b). El criterio debe
    reevaluarse a más tardar en la visita 3 cuando se disponga de los
    resultados de las visitas 1a y 2 o de las visitas 1b y 2.
    6. Control adecuado de la hipertensión con un inhibidor de la enzima
    convertidora de la angiotensina o un bloqueador del receptor de la
    angiotensina (a menos que no se considere apropiado para el
    participante) según lo sugerido por la «Guía práctica clínica para el
    tratamiento de la tensión arterial en la enfermedad renal crónica»
    (Clinical Practice Guideline for the Management of Blood Pressure in
    Chronic Kidney Disease) de la Kidney Disease Improving Global
    Outcomes (KDIGO) sin el uso de un diurético.
    7. Índice de masa corporal (IMC) entre 18 y 40 kg/m2 (inclusive) en el
    momento de la selección.
    8. Las participantes deben:
    • no estar embarazadas, en periodo de lactancia o amamantando.
    • ser o posmenopáusicas (definido como amenorrea durante ≥12 meses)
    o estériles mediante cirugía (definido como haberse sometido a una
    histerectomía y/o ooforectomía bilateral) o, si tienen capacidad para
    quedarse embarazadas, aceptar el uso de métodos anticonceptivos
    aceptables o practicar la abstinencia (solo si es el estilo de vida preferido
    y habitual de la participante) durante toda la duración del ensayo y
    durante 30 días después de la última dosis del medicamento del estudio.
    Los métodos anticonceptivos que pueden usarse durante el estudio son
    los siguientes:
    • anticonceptivos hormonales: anticonceptivos hormonales combinados
    (con estrógenos y progestágenos) con inhibición de la ovulación (p. ej.,
    oral, intravaginal, transdérmica); anticonceptivos hormonales (p. ej.,
    orales, inyectables o mediante implantes) solo con progestágenos
    • dispositivo intrauterino (DIU), incluidos los dispositivos intrauterinos
    con progestina
    • sistema intrauterino (SIU) de liberación hormonal
    • pareja sexual varón que se haya sometido a vasectomía al menos 3 meses antes de la selección y que haya obtenido un recuento de esperma
    negativo de seguimiento y sea la única pareja sexual
    • Ligadura de trompas bilateral
    • Procedimiento Essure® (oclusión de trompas)
    • preservativo masculino o femenino con espermicida (crema, espray,
    gel, supositorio o película de polímero)
    • diafragma, capuchón cervical o esponja anticonceptiva con
    espermicida (con o sin preservativo masculino)
    9. Los participantes varones deben acceder a usar un método
    anticonceptivo aceptable (véase la lista anterior) o practicar la
    abstinencia (solo si es el estilo de vida preferido y habitual del
    participante) durante toda la duración del ensayo y durante 30 días
    después de la última dosis del medicamento del estudio.
    10. Haber leído, comprendido y dado su consentimiento informado por
    escrito tras habérsele explicado la naturaleza del estudio y estar
    dispuesto/a cumplir los requisitos del protocolo y los procedimientos
    relacionados con el estudio.
    E.4Principal exclusion criteria
    1.Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] >7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant kidney disease, kidney cancer, transplanted kidney, single kidney, kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within 6 months prior to Screening.
    2.Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
    3.New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the participant.
    4.History of infection with human immunodeficiency virus (HIV) unless the participant is stable and doing well on a non-CYP interacting ART regimen and the participant has not required more than 2 changes in their ART regimen since treatment inception.
    5.History of clinically significant drug or alcohol abuse in the 2 years prior to Screening Visit 1a.
    6.Contraindications to or interference with MRI assessments (e.g., ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, or large abdominal/back tattoos). Investigator should seek MRI safety guidance from the local MRI facility.
    7.Any malignancy within 5 years prior to Screening except for basal cell carcinoma successfully treated with local therapy or malignancies that are considered by the Investigator not to affect participant survival (after discussion with the medical monitor).
    8.Medical history or findings that preclude safe participation in the trial or participants who are likely to be non-compliant with trial procedures in the opinion of the Investigator or medical monitor.
    9.Clinically significant liver disease or impairment or alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin values >1.2 x ULN during Screening. Note: This criterion will preliminarily be reviewed at Visit 2 based on Visit 1a and Visit 1b results (if Visit 1b is required). The criterion must be re-evaluated no later than Visit 3 when results for Visit 2 are available.
    10.Requirement for ongoing diuretic use.
    11.Participants who are currently taking, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John’s wort. If applicable, there should be a 14-day washout of these treatments prior to Visit 2.
    12.Prior use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., canagliflozin, dapagliflozin, empagliflozin, etc.) within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a SGLT2 inhibitor during the study.
    13. Prior use of a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor within the 2 months prior to Screening Visit 1a or expected need for initiation of treatment with a HIF-PH inhibitor during the study.
    14.Simvastatin at a total daily dose >10 mg or amlodipine at a total daily dose >5 mg.
    15.Prior use of tolvaptan or lixivaptan within the 2 months prior to Screening Visit 1a.
    16.Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin (except for diabetes), nicotinamide, bardoxolone, demeclocycline, or mTOR kinase inhibitors (e.g., everolimus, sirolimus, etc.) within the 2 months prior to Screening Visit 1a.
    17.Participants who have taken any investigational drug or used an investigational device within 30 days, or 5 half-lives, whichever is longer, prior to Screening Visit 1a or plan to participate in an interventional trial during the study.
    18.Hypovolemia on physical examination at Screening.
    19.Abnormal serum sodium concentration at Screening.
    20.Positive test results for hepatitis B surface antigen (HBsAg).
    21.Positive test results for hepatitis C (HCV) antibody (Anti-HCV), with the exception of participants for whom the reflex HCV RNA titer test is negative.
    22.Known sensitivity or idiosyncratic reaction to lixivaptan and/or its excipients.
    Diabetes avanzada (p. ej., hemoglobina glicosilada [HgbA1c] >7,5 % y/o
    glucosuria mediante tiras reactivas, proteinuria significativa [>300 mcg
    de albúmina/mg de creatinina]), otra enfermedad renal significativa,
    cáncer renal, riñón trasplantado, tener solo un riñón, cirugía renal en los
    6 últimos meses (incluido drenaje o fenestración quística) o daño renal
    agudo en los 6 meses anteriores a la selección.
    2. Incontinencia, vejiga hiperactiva o retención urinaria clínicamente
    significativas (p. ej., hiperplasia prostática benigna).
    3. Insuficiencia cardíaca de clase funcional 3 o 4 de la New York Heart
    Association u otros hallazgos electrocardiográficos (ECG) o cardíacos
    significativos que podrían suponer un riesgo para la seguridad del
    participante.
    4. Antecedentes de infección con el virus de la inmunodeficiencia
    humana (VIH), a menos que el participante esté estable y obteniendo
    buenos resultados al estar en tratamiento con una pauta de una terapia
    antirretroviral (TAR) que no interactúe con CYP y el paciente no haya
    requerido más de 2 cambios en su pauta de TAR desde el inicio del
    tratamiento.
    5. Antecedentes de consumo abusivo de alcohol o drogas clínicamente
    significativos en los 2 años anteriores a la visita 1a de la selección.
    6. Contraindicaciones o interferencia con las evaluaciones mediante RM
    (p. ej., prótesis de metal ferromagnético, pinzas de aneurisma,
    claustrofobia grave o tatuajes grandes en el abdomen o la espalda). El
    investigador debe solicitar orientación en cuanto a la seguridad de la RM
    por parte de la instalación local de RM.
    7. Cualquier neoplasia maligna en los 5 años anteriores a la selección,
    salvo carcinoma de células basales tratado satisfactoriamente con
    terapia local o neoplasias malignas que el investigador considere que no
    afectan a la supervivencia del participante (tras comentarlo con el
    monitor médico).
    8. Antecedentes o hallazgos médicos que impidan la participación en
    condiciones de seguridad en el ensayo o participantes que es probable que no cumplan con los procedimientos del ensayo a juicio del
    investigador o del monitor médico.
    9. Enfermedad renal o insuficiencia clínicamente significativas o valores
    de alanina aminotransferasa (ALT), aspartato aminotransferasa (AST) o
    bilirrubina total >1,2 x LSN durante la selección. Nota: Este criterio se
    revisará de forma preliminar en la visita 2 con base en los resultados de
    la visita 1a y la visita 1b (si se requiere la visita 1b). El criterio debe
    reevaluarse a más tardar en la visita 3 cuando se disponga de los
    resultados de la visita 2.
    10. Necesidad de uso continuado de diuréticos.
    11. Participantes que estén tomando actualmente o tengan previsto
    tomar inductores o inhibidores moderados o potentes de CYP2C8 o
    CYP3A4, incluido el uso habitual de zumo de pomelo, naranjas amargas o
    hierba de San Juan. Si procede, debe haber un periodo de reposo
    farmacológico de 14 días de dichos tratamientos antes de la visita 2.
    12. Uso previo de un inhibidor del cotransportador de sodio-glucosa tipo
    en los 2 meses anteriores a la visita 1a de la selección o necesidad
    prevista de inicio de un tratamiento con un inhibidor del SGLT2 durante
    el estudio.
    13. Uso previo de un inhibidor de prolil hidroxilasa del factor inducible
    por hipoxia (HIF-PH) en los 2 meses anteriores a la visita 1a de la
    selección o necesidad prevista de inicio de un tratamiento con un
    inhibidor de HIF-PH durante el estudio.
    14. Simvastatina a una dosis diaria total >10 mg o amlodipina a una
    dosis diaria total >5 mg.
    15. Uso previo de tolvaptán o lixivaptan en los 2 meses anteriores a la
    visita 1a de la selección.
    16. Uso previo de conivaptán, análogos de la somatostatina (p. ej.,
    lanreotida, pasireotida, octreotida, etc.), metformina (salvo para la
    diabetes), nicotinamida, bardoxolona, demeclociclina o inhibidores de
    mTOR (p. ej., everólimus, sirólimus, etc.) en los 2 meses previos a la
    visita 1a de la selección.
    17. Participantes que han tomado cualquier fármaco en fase de
    investigación o usado un dispositivo en fase de investigación en los 30
    días o 5 semividas (el periodo de mayor duración) anteriores a la visita
    1a de la selección o planeen participar en un ensayo intervencionista
    durante el estudio.
    18. Hipovolemia en la exploración física en la selección.
    19. Concentración de sodio sérica anómala en la selección.
    20. Resultados positivos en la prueba del antígeno de superficie de la
    hepatitis B (HBsAg).
    21. Resultados positivos en la prueba del anticuerpo del virus de la
    hepatitis C (Anti-VHC), salvo los participantes que tengan un resultado
    negativo en la prueba de valoración del ARN del VHC reflejo.
    22. Sensibilidad conocida o reacción idiosincrásica a lixivaptan y/o sus
    excipientes.
    E.5 End points
    E.5.1Primary end point(s)
    Part 1:
    •The primary endpoint is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Screening and Placebo Run-in Periods (Visits 1a/1b (if required), Visit 2, and Visit 3) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period I or, for participants who discontinue treatment prior to Visit 22, during the Follow-up Period 8 to 28 days following study drug treatment discontinuation).
    Part 1 Key Safety Endpoint
    •Incidence of serum ALT levels >3 x ULN in participants randomized to lixivaptan compared to those randomized to placebo.

    Part 2 Key Comparison Endpoint
    •The primary endpoint of Part 2 is the annualized change in eGFR calculated from the CKD-EPI equation for serum creatinine from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to final assessment (mean of 3 eGFR determinations obtained during Follow-up Period II).
    Part 2 Key Safety Endpoint:
    •Incidence of serum ALT levels > 3 x ULN in participants exposed to lixivaptan in Part 2.
    Parte 1:
    Criterio de valoración principal de la eficacia: Cambio anualizado en la
    TFGe calculado con la ecuación CKD-EPI para la creatinina sérica desde
    el inicio (media de 3 determinaciones de la TFGe obtenidas durante los
    periodos de selección y preinclusión con placebo [visitas 1a o 1b (si se
    requiere), visita 2 y visita 3] hasta la evaluación final [media de 3
    determinaciones de la TFGe obtenidas durante el periodo de seguimiento
    I o, en el caso de participantes que interrumpan el tratamiento antes de
    la visita 22, durante el periodo de seguimiento de 8 a 28 días tras la
    interrupción del tratamiento con el fármaco del estudio]).
    Criterio de valoración clave de la seguridad: Incidencia de los niveles
    séricos de ALT >2 x LSN en participantes aleatorizados a lixivaptan en
    comparación con aquellos aleatorizados al placebo.
    Parte 2:
    Criterio de valoración clave de comparación: Cambio anualizado en la
    TFGe desde el inicio (la media de las 3 mediciones de la TFGe obtenidas
    durante el periodo de seguimiento I) hasta la evaluación final posterior
    al tratamiento en la parte 2 (la media de las 3 mediciones de la TFGe
    obtenidas durante el periodo de seguimiento II).
    Criterio de valoración clave de la seguridad: Incidencia de los niveles
    séricos de ALT >3 x LSN en participantes expuestos a lixivaptan en la
    parte 2.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout this study, the safety of participants will be closely
    monitored by an independent data monitoring committee (DMC). The
    DMC will comprise three disease experts and a biostatistician and will be governed by a DMC Charter. A Data Monitoring Committee will review safety and study data at specified intervals for the duration of the study.
    A lo largo de este estudio, la seguridad de los participantes estará
    estrechamente
    monitoreado por un comité de monitoreo de datos independiente (DMC).
    los
    El DMC estará compuesto por tres expertos en enfermedades y un
    bioestadístico y se regirá por una Carta del DMC. Un Comité de Monitoreo
    de Datos revisará la seguridad y estudiará los datos a intervalos
    específicos durante la duración del estudio.
    E.5.2Secondary end point(s)
    Part 1:
    •The annualized rate of change (slope) in on-treatment eGFR, based on all on-treatment eGFR determinations during the Double-Blind, Randomized Treatment Period in Part 1, calculated from the CKD-EPI equation for serum creatinine;
    •The annualized rate of change from baseline in TKV, determined by MRI, during Follow-up Period I.

    Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
    •Treatment-emergent adverse events (TEAEs);
    •Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry, hematology and urinalysis);
    •Vital signs;
    •12-lead electrocardiograms (ECG).

    Part 2:
    •The annualized rate of change in eGFR (calculated from the CKD-EPI equation for serum creatinine) from baseline (mean of 3 eGFR determinations obtained during Follow-up Period I) to Follow-up Period II;
    •The annualized rate of change in TKV determined by MRI.

    Secondary Safety and tolerability of lixivaptan assessed through evaluation of:
    •Treatment-emergent adverse events (TEAEs);
    •Clinical laboratory findings (clinical chemistry including additional analyses of liver chemistry tests), hematology and urinalysis);
    •Vital signs;
    •12-lead electrocardiograms (ECG).
    Parte 1:
    • La tasa de cambio anualizada (pendiente) en la TFGe durante el
    tratamiento, basada en todas las determinaciones de la TFGe durante el
    tratamiento durante el Período de tratamiento aleatorizado doble ciego
    de la Parte 1, calculado a partir de la ecuación CKD-EPI para la creatinina
    sérica;
    • La tasa anualizada de cambio desde el inicio en TKV, determinada por
    MRI, durante el Período de seguimiento I.
    La seguridad secundaria y la tolerabilidad del lixivaptán se evaluaron
    mediante la evaluación de:
    • Eventos adversos emergentes del tratamiento (TEAE);
    • Hallazgos de laboratorio clínico (química clínica que incluye análisis
    adicionales de química hepática, hematología y análisis de orina);
    •Signos vitales;
    • Electrocardiogramas de 12 derivaciones (ECG).
    Parte 2:
    • La tasa anualizada de cambio en la TFGe (calculada a partir de la
    ecuación CKD-EPI para la creatinina sérica) desde el inicio (media de 3
    determinaciones de la TFGe obtenidas durante el Período de seguimiento
    I) hasta el Período de seguimiento II;
    • La tasa anualizada de cambio en TKV determinada por MRI.
    La seguridad secundaria y la tolerabilidad del lixivaptán se evaluaron
    mediante la evaluación de:
    • Eventos adversos emergentes del tratamiento (TEAE);
    • Hallazgos de laboratorio clínico (química clínica que incluye análisis
    adicionales de pruebas de química hepática), hematología y análisis de
    orina);
    •Signos vitales;
    • Electrocardiogramas de 12 derivaciones (ECG).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary efficacy endpoints will be displayed by study
    visit, using summary statistics including the number of observations, the mean, median, standard deviation, and range for continuous measures and counts and percentages for categorical measures. Actual values as well as change from baseline will be presented.
    Supportive and exploratory efficacy measures will be analyzed similarly as above. Details of the analysis methods will be outlined in the statistical analysis plan (SAP).
    In addition, a responder analysis (based on change in serum bile acid
    levels and bilirubin) will also be considered. The response definition and its appropriate analysis methodology will be outlined in the SAP for the study.
    Los criterios de valoración secundarios de eficacia se mostrarán por visita del estudio, utilizando estadísticas resumen que incluyen el número de observaciones,la media,la mediana,la desviación estándar y el rango para medidas continuas y recuentos y porcentajes para medidas categóricas.Se presentarán los valores reales, así como el cambio desde la línea de base. Las medidas de eficacia de apoyo y exploratorias se analizarán de forma similar a la anterior.Los detalles de los métodos de análisis se describirán en el plan de análisis estadístico (SAP). Además,un análisis de respondedores (basado en el cambio en los ácidos biliares séricos niveles y bilirrubina) también se considerarán. La definición de respuesta y su metodología de análisis adecuada se describirán en el SAP para el estudio.
    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 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) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Study in two parts: Part 1 double blind placebo controlled and Part 2 open label
    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 concerned70
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA70
    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
    Brazil
    Canada
    Chile
    Colombia
    Georgia
    Israel
    Mexico
    Peru
    Serbia
    Turkey
    Ukraine
    United States
    Belgium
    Bulgaria
    France
    Hungary
    Italy
    Poland
    Romania
    Slovakia
    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
    LVLS
    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 months6
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days7
    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: 1200
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 state62
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 372
    F.4.2.2In the whole clinical trial 1200
    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
    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 Decision2022-01-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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