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    Summary
    EudraCT Number:2014-005012-42
    Sponsor's Protocol Code Number:747-302
    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:2015-10-30
    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 number2014-005012-42
    A.3Full title of the trial
    A Phase 3b, Double Blind, Randomized, Placebo Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cirrhosis
    Estudio de fase 3b, doble ciego, randomizado, controlado con placebo, multicéntrico que evalúa el efecto del ácido obeticólico en los resultados clínicos en pacientes con cirrosis biliar primaria.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3b clinical trial to measure the effect of Obeticholic acid against a placebo, in conjunction with standard treatment, on selected clinical measurements in patients with the liver disease, Primary Biliary Cirrhosis.
    Un ensayo clínico de fase 3b para medir el efecto del ácido obeticólico contra placebo, en conjunción con un tratamiento estándar, en mediciones clínicas seleccionadas en pacientes con enfermedades de hígado, cirrosis biliar primaria.
    A.4.1Sponsor's protocol code number747-302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02308111
    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 SponsorIntercept Pharmaceuticals 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 supportIntercept Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationChiltern International Spain
    B.5.2Functional name of contact pointRicardo Diaz - General Director
    B.5.3 Address:
    B.5.3.1Street AddressCentro Empresarial Euronova 3, Ronda de Poniente 10 ? 2ª Planta
    B.5.3.2Town/ cityTres Cantos, Madrid
    B.5.3.3Post code28760
    B.5.3.4CountrySpain
    B.5.4Telephone number+34911872700
    B.5.5Fax number+34911872849
    B.5.6E-mailspain.regulatory@chiltern.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/753
    D.3 Description of the IMP
    D.3.1Product nameObeticholic acid
    D.3.2Product code OCA, INT-747
    D.3.4Pharmaceutical form 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 INNObeticholic Acid
    D.3.9.1CAS number 459789-99-2
    D.3.9.2Current sponsor code6-ECDCA
    D.3.9.3Other descriptive name6?-ethylchenodeoxycholic acid (6-ECDCA), OCA, INT-747
    D.3.9.4EV Substance CodeSUB91981
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/753
    D.3 Description of the IMP
    D.3.1Product nameObeticholic acid
    D.3.2Product code OCA, INT-747
    D.3.4Pharmaceutical form 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 INNObeticholic Acid
    D.3.9.1CAS number 459789-99-2
    D.3.9.2Current sponsor code6-ECDCA
    D.3.9.3Other descriptive name6?-ethylchenodeoxycholic acid (6-ECDCA), OCA, Int-747
    D.3.9.4EV Substance CodeSUB91981
    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 placeboTablet
    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
    Primary Biliary Cirrhosis
    Cirrosis biliar primaria
    E.1.1.1Medical condition in easily understood language
    Primary Biliary Cirrhosis is a rare, chronic autoimmune liver disease characterized by both liver and biliary tract lesions that progress to cirrhosis and other complications.
    La cirrosis biliar primaria es una enfermedad hepática crónica autoinmune rara caracterizada por lesiones tanto en hígado como en el tracto biliar que progresan dando cirrosis y otras complicaciones.
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10036680
    E.1.2Term Primary biliary cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To assess the effect of OCA compared to placebo, in conjunction with established local standard of care, on clinical outcomes in subjects with primary biliary cirrhosis (PBC) as measured by time to first occurrence of any of the following adjudicated events, derived as a composite event endpoint:
    a. Death (all-cause).
    b. Liver transplant.
    c. Model of end stage liver disease (MELD) score ?15.
    d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
    i. Variceal bleed.
    ii. Encephalopathy (as defined by a West Haven score of ?2).
    iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis).
    e.Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least twice in a month).
    f. Hepatocellular carcinoma confirmed by 2 complimentary imaging modalities.
    1. Evaluar el efecto del AOC comparado con un placebo, administrado junto con el tratamiento de referencia establecido a nivel local, en los resultados clínicos de sujetos con CBP, que se mide en función del tiempo transcurrido hasta la aparición por primera vez de cualquiera de los siguientes acontecimientos determinantes, derivados como criterio de valoración compuesto de acontecimientos:
    a.Fallecimiento (por cualquier causa)
    b.Trasplante de hígado
    c.Puntuación del modelo de hepatopatía terminal(MELD) ?15
    d.Hospitalización (definida como una estancia de 24 h o más) por un nuevo brote o recurrencia de:
    i.Hemorragia digestiva por rotura de varices esofágicas
    ii.Encefalopatía (definida por una puntuación de West Haven ?2)
    iii.Peritonitis bacteriana espontánea (confirmada por paracentesis diagnóstica)
    e.Ascitis no controlada (ascitis resistente a diuréticos que requiere paracentesis terapéutica con una frecuencia mínima de 2 veces al mes)
    f.Carcinoma hepatocelular (..)
    E.2.2Secondary objectives of the trial
    1. To assess the effect of OCA compared to placebo on time to first occurrence of each individual component of the primary endpoint as listed above and also to include liver related death.
    2. To assess the effect of OCA compared to placebo on disease progression via the following:
    a. Liver biochemistry
    b. Markers of inflammation and fibrosis
    3. To assess the effect of OCA compared to historical controls on liver-related clinical outcomes.
    4. To assess the pharmacokinetics of OCA and its conjugates in a subset of subjects.
    5. To assess health outcomes and pharmacoeconomics including cost-effectiveness, resource utilization, and quality of life measures in subjects treated with OCA compared to placebo.
    6. To assess the safety and tolerability in subjects treated with OCA compared to placebo.
    1. Evaluar el efecto del AOC comparado con un placebo en el momento de la primera manifestación de cada uno de los componentes del criterio de valoración principal enumerados anteriormente, incluyendo también el de muerte de origen hepático.
    2. Evaluar el efecto del AOC comparado con un placebo en la evolución de la enfermedad a través de lo siguiente:
    a.Bioquímica hepática
    b.Marcadores de inflamación y fibrosis
    3. Evaluar el efecto del AOC comparado con los controles históricos en los resultados clínicos hepáticos.
    4. Evaluar la farmacocinética del AOC y sus conjugados en un subconjunto de sujetos.
    5. Evaluar los resultados sobre la salud y los factores farmacoeconómicos, entre otros la rentabilidad, utilización de recursos y la calidad de vida de los sujetos tratados con AOC en comparación con los que recibieron el placebo.
    6. Evaluar la seguridad y la tolerancia en sujetos tratados con AOC comparadas con el placebo.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The following title is mentioned in the Patient Informed Consent but not on the protocol where a description of the genetic s study is contained:

    "Optional Genetics Research Study: A Phase 3b, Double Blind, Randomized, Placebo Controlled, Multicenter Study Evaluating the Effect of Obeticholic Acid on Clinical Outcomes in Subjects with Primary Biliary Cirrhosis"

    A genetics study will be conducted in a subset of subjects who provide consent for analyses of these samples. Genetics samples will be collected at Day 0 and every other year beginning at Month 12.

    A genetics study for single-nucleotide polymorphisms (SNPs) that may be involved in PBC will be conducted for subjects and at study sites willing to provide samples at Day 0, Month 12, and every other year at the yearly visits thereafter. RNA expression resulting from treatment with OCA will be assessed at indicated timepoints during the study. Subjects will be permitted to decline to provide a blood sample for the genetics study, without affecting their involvement in the study. Clinical Research Ethic committees review and approval will be required and willing subjects must specifically consent to participate in this evaluation. The samples will be stored for up to 1 year after the end of the study and destroyed after 1 year if not analyzed.
    El siguiente título se menciona en el consentimiento informado del paciente, pero no en el protocolo en el que se incluye una descripción del estudio genético:
    "Estudio genético opcional: Estudio de fase 3b, doble ciego, randomizado, controlado con placebo, multicéntrico que evalúa el efecto del ácido obeticólico en los resultados clínicos en pacientes con cirrosis biliar primaria".

    Un subestudio de genética se llevará a cabo en un subgrupo de pacientes que hayan consentido a este análisis de sus muestras. Las muestras para la genética se recogerán en el Día 0 y cada 2 años a partir del Mes 12.

    Un estudio de la genética de los polimorfismos de un solo nucleótido (SNP) que pueden estar implicados en la CBP se llevará a cabo para los sujetos y en los sitios de estudio dispuestos a proporcionar muestras en el día 0, Mes 12, y cada dos años en las visitas anuales a partir de entonces. Expresión de ARN que resulta del tratamiento con AOC se evaluará en los puntos de tiempo indicados durante el estudio. A los pacientes se les permitirá negarse a proporcionar una muestra de sangre para el estudio de genética, sin afectar a su participación en el estudio. Se requerirá la revisión y aprobación por parte de los comités éticos de investigación clínica y los pacientes dispuestos a participar esta evaluación deben consentir específicamente. Las muestras serán almacenadas por hasta 1 año después del final del estudio y destruidas después de 1 año si no se analizan.
    E.3Principal inclusion criteria
    1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases [AASLD] and the European Association for the Study of the Liver [EASL] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ?2 of the following 3 diagnostic factors:
    -History of elevated ALP levels for at least 6 months
    -Positive antimitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
    -Liver biopsy consistent with PBC
    2. A mean total bilirubin >ULN and ?3x ULN and/or a mean ALP >5x ULN
    3. Age ?18 years
    4. Either is not taking UDCA (no UDCA dose in the past ?3 months) or has been taking UDCA for at least 12 months with a stable dose for ?3 months prior to Day 0
    5. Contraception: Female subjects must be postmenopausal, surgically sterile, or if premenopausal (and not surgically sterile), be prepared to use ?1 effective method of contraception during the study and for 30 days after the end of treatment visit. Effective methods of contraception are considered to be those listed below:
    -Double barrier method, ie, (a) condom (male or female) or (b) diaphragm, with spermicide; or
    -Intrauterine device (IUD); or
    -Vasectomy (partner), or
    -Hormonal (eg, contraceptive pill, patch, intramuscular implant or injection, or
    -Abstinence, if in line with the preferred and usual lifestyle of the subject)
    6. Must provide written informed consent and agree to comply with the study protocol.
    1. Diagnóstico confirmado o probable de CBP (según las directrices de práctica de la Asociación Estadounidense para el Estudio de las Enfermedades Hepáticas [AASLD, pos sus siglas en inglés] y la Asociación Europea para el Estudio del Hígado [EASL, por sus siglas en inglés] ; Lindor 2009; EASL 2009), demostrado por la presencia de ?2 de los siguientes 3 factores de diagnóstico:
    - Antecedentes de niveles elevados de FA durante un mínimo de 6 meses.
    - Valor positivo de anticuerpos antimitocondriales (AAM) o bien, si los AAM son negativos o tienen un valor bajo (<1:80), anticuerpos específicos de la CBP (anti-GP210 o anti-SP100 o anticuerpos contra los principales componentes del M2 [PDC-E2, complejo de la deshidrogenasa del ácido 2-oxo-glutárico]).
    -Biopsia hepática compatible con CBP.
    2. Bilirrubina total media >LSN y ?3x LSN o FA media >5x LSN.
    3. Edad ?18 años.
    4. El sujeto no está tomando AUDC (no ha recibido una dosis de AUDC en los últimos ?3 meses) o ha tomado AUDC durante al menos 12 meses con una dosis estable durante ?3 meses antes del día 0.
    5. Anticoncepción: las mujeres deben ser posmenopáusicas, quirúrgicamente estériles o, en el caso de ser premenopáusicas (no quirúrgicamente estériles), deben estar dispuestas a utilizar ?1 de un método anticonceptivo eficaz durante todo el estudio y hasta 30 días después de la consulta de finalización del tratamiento. Se consideran métodos anticonceptivos efectivos los enumerados a continuación:
    -Método de doble barrera, esto es, (a) preservativo (masculino o femenino), (b) diafragma con espermicida o
    -Dispositivo intrauterino (DIU); o
    -Vasectomía (de la pareja).
    -Hormonales (p. ej., píldora, parche, implante intramuscular o inyección anticonceptiva), o
    -Abstinencia (si este método es compatible con el estilo de vida habitual o preferido del sujeto).
    6. Los sujetos deben otorgar su consentimiento informado por escrito y aceptar cumplir el protocolo del estudio.
    E.4Principal exclusion criteria
    1. History or presence of other concomitant liver diseases including:
    a. Hepatitis C virus infection
    b. Active hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
    c. Primary sclerosing cholangitis
    d. Alcoholic liver disease
    e. Definite autoimmune liver disease or overlap hepatitis
    f. Nonalcoholic steatohepatitis
    g. Gilbert ? s Syndrome
    2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
    a. History of liver transplant, current placement on a liver transplant list, or current MELD score >12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
    b. Cirrhosis with complications, including history (within the past 12 months) or presence of:
    i. Variceal bleeding
    ii. Uncontrolled ascites
    iii. Encephalopathy
    iv. Spontaneous bacterial peritonitis
    c. Known or suspected hepatocellular carcinoma
    d. Prior transjugular intrahepatic portosystemic shunt procedure
    e. Hepatorenal syndrome (type I or II) or Screening (visit 1 or 2) serum creatinine >2 mg/dL (178 µmol/L)
    3. Mean
    4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
    5. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)
    6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
    7. Known history of human immunodeficiency virus infection
    8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months)
    9. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
    10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0
    11. Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study
    12. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
    13. History of known or suspected clinically significant hypersensitivity to OCA or any of its components
    1. Antecedentes o presencia de otras enfermedades hepáticas concurrentes, entre ellas:
    a. Infección por virus de la hepatitis C.
    b. Infección por hepatitis B activa; sin embargo, los sujetos con seroconversión (antígeno de superficie de la hepatitis B y antígeno "e" negativo de la hepatitis B) pueden ser incluidos en este estudio previa consulta con el supervisor médico.
    c. Colangitis esclerosante primaria.
    d. Hepatitis alcohólica.
    e. Hepatopatía autoinmunitaria patente o hepatitis superpuesta.
    f. Esteatohepatitis no alcohólica
    g. Síndrome de Gilbert.
    2. Presencia de complicaciones clínicas de la CBP o descompensación hepática clínicamente significativa, que incluye:
    a. Antecedentes de trasplante hepático, inclusión vigente en una lista de trasplante hepático o puntuación actual >12 en la escala MELD. Los sujetos incluidos en una lista de espera para trasplante a pesar de encontrarse en una fase temprana de la enfermedad (por ejemplo, de acuerdo con las directrices regionales) pueden cumplir los requisitos siempre que no cumplan algún otro criterio de exclusión.
    b. Cirrosis con complicaciones, incluidos antecedentes (en los últimos 12 meses) o presencia de:
    i. Varices sangrantes
    ii. Ascitis no controlada
    iii. Encefalopatía
    iv. Peritonitis bacteriana espontánea
    c. Sospecha o certeza de carcinoma hepatocelular.
    d. Intervención previa de derivación portosistémica intrahepática transyugular.
    e. Síndrome hepatorrenal (tipo I o II) o creatinina sérica en el momento de la selección (consulta 1 o 2) >2mg/dl (178 µmol/l).
    3. Media
    4. Sujetos que se han sometido a intervenciones de derivación gástrica (la banda gástrica ajustable es aceptable) o resección ileal, o que tengan previsto someterse a alguno de estos procedimientos.
    5. Otras afecciones médicas que puedan disminuir la esperanza de vida, como por ejemplo cánceres conocidos (excepto carcinomas in situ u otras afecciones estables relativamente benignas como la leucemia linfática crónica).
    6. En las mujeres: tienen previsto quedarse embarazadas, están embarazadas o reciben un resultado positivo en la prueba de embarazo en orina (confirmada por una prueba de embarazo positiva en suero), o se encuentran en período de lactancia.
    7. Antecedentes conocidos de infección por el virus de inmunodeficiencia humana.
    8. Afecciones médicas que pudieran causar aumentos de la FA de origen no hepático (por ejemplo, la enfermedad de Paget o fracturas en un lapso de 3 meses).
    9. Otras afecciones médicas clínicamente significativas que no estén bien controladas o para las que se prevean cambios en las necesidades de medicación durante el estudio.
    10. Antecedentes de consumo excesivo de alcohol u otras sustancias en el período de 1 año anterior al día 0.
    11. Participación en otro estudio de un producto en fase de investigación o de un producto biológico o sanitario experimental en los 30 días anteriores a la selección. Se permite la participación en un estudio anterior del AOC con un período de reposo farmacológico de 3 meses previo a la inscripción en este estudio.
    12. Inestabilidad o incompetencia mental, que plantee dudas sobre la validez del consentimiento informado o la capacidad de cumplimiento terapéutico en el estudio.
    13. Antecedentes de hipersensibilidad clínicamente significativa conocida o sospechada al AOC o a cualquiera de sus componentes.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the time to first occurrence of one of the following post randomization:
    a. Death (all-cause)
    b. Liver transplant
    c. Model of end stage liver disease (MELD) score ?15
    d. Hospitalization (as defined by a stay of 24 hours or greater) for new onset or recurrence of:
    i. Variceal bleed
    ii. Encephalopathy (as defined by a West Haven score of ?2)
    iii. Spontaneous bacterial peritonitis (confirmed by diagnostic paracentesis)
    e. Uncontrolled ascites (diuretic resistant ascites requiring therapeutic paracentesis at a frequency of at least
    El criterio de valoración principal de la eficacia será el tiempo transcurrido hasta la primera manifestación de uno de los siguientes acontecimientos posteriores a la aleatorización:
    a. Fallecimiento (por cualquier causa)
    b. Trasplante de hígado
    c. Puntuación del modelo de hepatopatía terminal (MELD) ?15
    d. Hospitalización (definida como una estancia de 24 horas o más) por un nuevo brote o recurrencia de:
    i. Varices sangrantes
    ii. Encefalopatía (definida por una puntuación de West Haven ?2)
    iii. Peritonitis bacteriana espontánea (confirmada por paracentesis)
    e. Ascitis no controlada (ascitis resistente a diuréticos que requiere paracentesis terapéutica con una frecuencia mínima de dos veces al mes)
    E.5.1.1Timepoint(s) of evaluation of this end point
    8 years
    8 años
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Analyses
    The key secondary efficacy endpoints are as follows:
    a. Time to first occurrence of MELD score ?15
    b. Time to liver transplant or death (all-cause)
    c. Change from Baseline in total bilirubin at end of study
    d. Change from Baseline in ALP at end of study
    Other Efficacy Analyses
    The following secondary efficacy analyses will compare OCA to placebo on time to the following events:
    a. Each component of the primary efficacy endpoint (except MELD score ? 15 which is listed above)
    b. Development of varix/varices
    c. Liver-related death
    d. Liver-related death or liver transplant
    e. Liver-related death, liver transplant, or MELD score ?15
    Safety Analysis
    Safety data, including AEs, vitals, electrocardiogram, and clinical laboratory results will compare OCA and placebo using the Safety Population.

    Health outcomes and pharmacokinetic analyses
    A continuación se presentan los principales criterios de valoración secundarios:
    a. Tiempo transcurrido hasta la primera manifestación de una puntuación de la escala MELD ?15
    b. Tiempo transcurrido hasta el trasplante de hígado o la muerte (por cualquier causa)
    c. Cambios en la bilirrubina total desde el valor de referencia al finalizar el estudio
    d. Cambios en la FA desde el valor de referencia al finalizar el estudio.
    Otros análisis de la eficacia
    Los siguientes análisis secundarios de la eficacia compararán el AOC con el placebo en cuanto al tiempo de manifestación de los siguientes acontecimientos:
    a. Cada componente del criterio de valoración principal de la eficacia (excepto la puntuación de MELD ?15 indicada anteriormente)
    b. Aparición de varices
    c. Muerte de origen hepático
    d. Muerte de origen hepático o trasplante de hígado
    e. Muerte de origen hepático, trasplante de hígado o puntuación de la escala MELD ?15.
    Análisis de la seguridad
    Los datos de seguridad, incluidos los AA, las constantes vitales, el electrocardiograma y los resultados analíticos compararán el AOC con el placebo utilizando la población de seguridad.

    Los resultados de salud y los análisis farmacocinéticos
    E.5.2.1Timepoint(s) of evaluation of this end point
    8 years
    8 años
    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 Yes
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    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
    Argentina
    Australia
    Austria
    Belgium
    Bulgaria
    Canada
    Chile
    Denmark
    Estonia
    Finland
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Lithuania
    Mexico
    Netherlands
    New Zealand
    Poland
    Serbia
    Spain
    Sweden
    Switzerland
    Turkey
    United Kingdom
    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 patient last visit
    Última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    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 years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 228
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 122
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 350
    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. Patients will revert to standard of care treatment
    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 Decision2015-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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