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    Summary
    EudraCT Number:2021-001810-13
    Sponsor's Protocol Code Number:GSN000350
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-19
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2021-001810-13
    A.3Full title of the trial
    TRANSFORM: A 52-week, Randomized, Placebo controlled, Double blind, Adaptive Phase 2b/3 Trial of Setanaxib with a 52 week Extension Phase in Patients with Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness
    TRANSFORM: Ensayo clínico de fase IIb/III, adaptativo, doble ciego, aleatorizado, controlado con placebo y de 52 semanas de duración de setanaxib con una fase de extensión de 52 semanas en pacientes con colangitis biliar primaria (CBP) y rigidez hepática elevada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2b/3 Trial of Setanaxib with a 52 week Extension Phase in Patients with PBC and Elevated Liver Stiffness
    Ensayo de fase IIb/III de setanaxib con una fase de extensión de 52 semanas en pacientes con CBP y rigidez hepática elevada
    A.3.2Name or abbreviated title of the trial where available
    TRANSFORM
    A.4.1Sponsor's protocol code numberGSN000350
    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 SponsorGenkyotex Suisse SA
    B.1.3.4CountrySwitzerland
    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 supportCalliditas Therapeutics AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPRA Health Sciences
    B.5.2Functional name of contact pointBenedicte Moal Rowland
    B.5.3 Address:
    B.5.3.1Street Address500 South Oak Way, Green Park
    B.5.3.2Town/ cityReading
    B.5.3.3Post codeRG2 6AD
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44118918 1100
    B.5.6E-mailrowlandbenedicte@prahs.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/3/20/2387
    D.3 Description of the IMP
    D.3.1Product nameSETANAXIB
    D.3.2Product code GKT137831
    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 INNSetanaxib
    D.3.9.1CAS number 1218942-37-0
    D.3.9.2Current sponsor codeGKT137831
    D.3.9.3Other descriptive nameGYPP-06 (GKT137831 free base), C10071301-D
    D.3.9.4EV Substance CodeSUB195304
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number400
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Biliary Cholangitis (PBC) and Elevated Liver Stiffness
    Colangitis biliar primaria (CBP) y rigidez hepática elevada
    E.1.1.1Medical condition in easily understood language
    Liver disease caused by autoimmune attack on the small to medium bile ducts
    Enfermedad hepática causada por un ataque autoinmune a los conductos biliares pequeños y medianos
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10080429
    E.1.2Term Primary biliary cholangitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of setanaxib on biochemical response at Week 52 in patients with PBC and with elevated liver stiffness and intolerance or inadequate response to ursodeoxycholic acid (UDCA)
    Evaluar el efecto de setanaxib sobre la respuesta bioquímica en la semana 52 en pacientes con CBP y con rigidez hepática elevada e intolerancia o respuesta insuficiente al ácido ursodesoxicólico (AUDC)
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of setanaxib on liver stiffness at Week 52
    - To evaluate the effect of setanaxib on fatigue at Week 52
    - To evaluate the effect of setanaxib on pruritus at Week 52
    - To evaluate the safety and tolerability of setanaxib over a 52 week treatment period
    - To further evaluate the safety and tolerability of setanaxib in patients with PBC and with elevated liver stiffness and intolerance or inadequate response to UDCA (Extension phase)
    - Evaluar el efecto de setanaxib sobre la rigidez hepática en la semana 52
    - Evaluar el efecto de setanaxib sobre la fatiga en la semana 52
    - Evaluar el efecto de setanaxib sobre el prurito en la semana 52
    - Evaluar la seguridad y tolerabilidad de setanaxib durante un periodo de tratamiento de 52 semanas
    - Evaluar en mayor profundidad la seguridad y tolerabilidad de setanaxib en pacientes con CBP y con rigidez hepática elevada e intolerancia o respuesta inadecuada al AUDC
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female patient aged ≥18 years, inclusive at the time of informed consent.
    2. Willing and able to give written informed consent and to comply with the requirements of the study.
    3. Definite or probable PBC diagnosis as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:
    a. Documented history of elevated ALP levels ≥1.67×ULN of the local reference range
    b. Positive AMA titer or, if AMA negative or in low titer (<1:80), positive 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])
    c. Liver biopsy consistent with PBC.
    4. Serum ALP ≥1.67×ULN at Screening.
    One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for patients who do not meet this inclusion criterion at Screening Visit 1. If this inclusion criterion is then met at Screening Visit 2, the patient may be eligible for the study.
    5. Liver stiffness measured by transient elastography (FibroScan®) of ≥8.8 kPa at Screening and at Baseline (a minimum of 10 valid readings, with at least a 70% success rate and an interquartile range of ≤30% of the median value, are taken with the results expressed in kilopascals [kPa]).
    6. UDCA prescriptional dose use for the past 6 months (at a stable dose for >3 months prior to Screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to Screening).
    7. For patients receiving OCA, fenofibrate, or bezafibrate treatment for at least 6 months and stable dose for >3 months prior to Screening.
    8. For patients intolerant to OCA, OCA must have been discontinued >3 months prior to Screening.
    9. For patients previously treated with bezafibrate or fenofibrate, these agents must have been be discontinued >3 months prior to Screening.
    10. Female patients of childbearing potential must use a highly effective method of contraception to prevent pregnancy for ≥4 weeks before Randomization and must agree to continue strict contraception up to 90 days after the last dose of IMP.
    a. For the purposes of this trial, women of childbearing potential are defined as “All female patients after menarche unless they are postmenopausal for at least 2 years or are surgically sterile.”
    b. For female patients ≤55 years of age who are considered postmenopausal and who are not on concomitant estrogen replacement therapy, confirmation of postmenopausal status will be required with follicle stimulating hormone (FSH) test results in the postmenopausal range for age at Screening.
    c. Highly effective contraception is defined as use of 2 barrier methods (eg, female diaphragm and male condoms) or use of at least 1 barrier method in combination with spermicide, an intrauterine device or hormonal contraceptives (eg, implant or oral).
    11. Female patients of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline/Randomization before dosing.
    12. Male patients with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the Investigator, such as an established form of hormonal contraceptive, a diaphragm or cervical/vault cap, or intrauterine device. This requirement begins at the time of informed consent and ends 90 days after receiving the last dose of IMP.
    13. Male patients must be willing not to donate sperm, and female study participants must be willing not to donate eggs, from Baseline until 90 days after the last dose of IMP.
    1. Pacientes de ambos sexos con ≥18 años de edad, inclusive, en el momento del consentimiento informado.
    2. Está dispuesto y es capaz de proporcionar consentimiento informado por escrito y de cumplir con los requisitos del estudio.
    3. Diagnóstico de CBP definitiva o probable, según lo demostrado por la presencia de ≥2 de los 3 factores diagnósticos siguientes:
    a. Antecedentes documentados de niveles elevados de FA ≥1,67 × LSN del intervalo de referencia local.
    b. Título de AMA positivo o, si es negativo para AMA o presenta un título bajo (<1:80), positivo en anticuerpos específicos de CBP (anti-GP210 y/o anti-SP100 y/o anticuerpos contra los principales componentes de M2 [PDC-E2, complejo ácido-2 oxoglutárico deshidrogenasa])
    c. Biopsia hepática compatible con CBP.
    4. FA sérica ≥1,67 × LSN en la selección.
    Se puede repetir la extracción de muestras de sangre (con análisis por parte del laboratorio central) a criterio del investigador en la visita de selección 2 para los pacientes que no cumplan este criterio de inclusión en la visita de selección 1. Si se cumple este criterio de inclusión en la visita de selección 2, el paciente puede ser apto para el estudio.
    5. Rigidez hepática medida mediante elastografía transitoria (FibroScan®) de ≥8,8 kPa en la selección y al inicio (se obtienen un mínimo de 10 lecturas válidas, con una tasa de éxito de al menos el 70 % y un intervalo intercuartil de ≤30 % con respecto al valor de la mediana, con los resultados expresados en kilopascales [kPa]).
    6. Uso de una dosis prescrita de AUDC durante los últimos 6 meses (a una dosis estable durante >3 meses antes de la selección) O ser intolerantes al AUDC (última dosis de AUDC >3 meses antes de la selección).
    7. En el caso de los pacientes que estén recibiendo tratamiento con ACO, fenofibrato o bezafibrato durante al menos 6 meses y a una dosis estable durante >3 meses antes de la selección.
    8. En el caso de los pacientes intolerantes al ACO, este debe haberse interrumpido >3 meses antes de la selección.
    9. En el caso de los pacientes tratados previamente con bezafibrato o fenofibrato, estos fármacos deben haberse interrumpido >3 meses antes de la selección.
    10. Las pacientes con capacidad de concebir deben utilizar un método anticonceptivo altamente eficaz para evitar el embarazo durante ≥4 semanas antes de la aleatorización y deben aceptar seguir utilizando métodos anticonceptivos estrictos hasta 90 días después de la última dosis del PEI.
    a. Para los fines de este ensayo, las mujeres con capacidad de concebir se definen como “Todas las pacientes después de la menarquia, a menos que sean posmenopáusicas durante al menos 2 años o sean quirúrgicamente estériles”.
    b. En el caso de las pacientes de sexo femenino de ≤55 años de edad consideradas posmenopáusicas y que no reciban tratamiento sustitutivo de estrógenos de forma concomitante, se requerirá confirmación del estado posmenopáusico con resultados de la prueba de la hormona foliculoestimulante (FSH) en el intervalo posmenopáusico para la edad en la selección.
    c. La anticoncepción altamente eficaz se define como el uso de 2 métodos de barrera (p. ej., diafragma femenino y preservativos masculinos) o el uso de al menos 1 método de barrera en combinación con espermicida, un dispositivo intrauterino o anticonceptivos hormonales (p. ej., implante u oral).
    11. Las pacientes con capacidad de concebir deben tener un resultado negativo en la prueba de embarazo en suero en la selección y un resultado negativo en la prueba de embarazo en orina al inicio/en la aleatorización antes de la administración.
    12. Los pacientes varones con parejas de sexo femenino con capacidad de concebir deben estar dispuestos a utilizar un preservativo y exigir a su pareja el uso de un método anticonceptivo adecuado adicional aprobado por el investigador, como un método anticonceptivo hormonal establecido, un diafragma, un capuchón cervical o un dispositivo intrauterino. Este requisito comienza en el momento del consentimiento informado y finaliza 90 días después de recibir la última dosis del PEI.
    13. Los pacientes varones deben estar dispuestos a no donar esperma, y las participantes del estudio deben estar dispuestas a no donar óvulos, desde el inicio hasta 90 días después de la última dosis del PEI.
    E.4Principal exclusion criteria
    1. A positive pregnancy test or breastfeeding for female patients.
    2. Any historical or current hepatic decompensation event defined as variceal/portal hypertension bleed and/or hepatic encephalopathy, spontaneous bacterial peritonitis, ascites requiring treatment, or liver transplantation list inclusion.
    3. History of liver transplantation, current placement on a liver transplant list or current MELD score of ≥12 unless the patient is on anticoagulant therapy, or a Child Pugh Score of ≥6.
    4. Cirrhosis with complications, including history or presence of hepatocellular carcinoma.
    5. Total bilirubin >2×ULN. In case of total bilirubin elevation >ULN the Screening serum albumin must be within the reference range.
    One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for patients who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the patient may be eligible for the study.
    6. Plasma ALT >3×ULN and/or AST >3×ULN.
    One repeat blood sampling (with analysis by the central laboratory) can be performed at the discretion of the Investigator at Screening Visit 2 for patients who meet this exclusion criterion at Screening Visit 1. If this exclusion criterion is not met at Screening Visit 2, the patient may be eligible for the study.
    7. INR >1.2 unless patient is on anticoagulant therapy.
    8. Estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2, as calculated by the central laboratory using the chronic kidney disease epidemiology collaboration (CKD EPI) equation.
    9. Thyroid stimulating hormone >ULN at Screening.
    10. Competing etiology for liver disease (eg, hepatitis C [unless effectively cured of hepatitis C, with a sustained virologic response for at least 6 months prior to Screening], active hepatitis B [HBsAg positive], nonalcoholic steatohepatitis [NASH], alcoholic liver disease, autoimmune hepatitis, autoimmune hepatitis PBC overlap syndrome, primary sclerosing cholangitis, Gilbert’s Syndrome).
    11. Medical conditions that could cause nonhepatic increases in ALP (eg, Paget's disease).
    12. Known history of HIV infection. If the anti-HIV antibody test is positive, HIV RNA negativity has to be confirmed by the central laboratory.
    13. Surgery (eg, stomach bypass) or medical condition that might significantly affect absorption of medicines (as judged by the Investigator).
    14. Positive urine drug screen (if not due to prescriptional use of a concomitant medication, as confirmed by the Investigator) at Screening.
    15. Patients receiving prohibited medications within 3 months of Screening Visit 1 including oral and systemic corticosteroids (see Section 6.6 for exceptions), colchicine, mycophenolate mofetil, azathioprine, methotrexate, sulfasalazine, leflunomide, cyclophosphamide, valproate, isoniazid, or nitrofurantoin. Any biologic agent within 12 weeks or 5 half lives prior to Screening, whichever is longer. In the case of rituximab, use within 168 days (24 weeks) of Screening is exclusionary. See the complete list of prohibited medications in Section 6.6.
    16. Treatment with any investigational agent within 12 weeks of Screening Visit 1 or 5 half-lives of the IMP (if known) (whichever is longer) or current enrollment in an interventional clinical trial.
    17. Evidence of any of the following cardiac conduction abnormalities: A QTc Fredericia interval >450 milliseconds for males or >470 milliseconds for females, as calculated by the central reader. Patients with a second or third degree atrioventricular block are to be excluded.
    18. Treatment or planned treatment, with a pacemaker, implanted cardioverter defibrillator, or other implanted electronic device.
    19. History of a malignancy within 5 years of Screening with the following exceptions:
    a. Adequately treated carcinoma in situ of the cervix
    b. Adequately treated basal or squamous cell cancer or other localized nonmelanoma skin cancer.
    20. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Screening Visit 1.
    21. A history of bone marrow disorder including aplastic anemia, or any current marked anemia defined as hemoglobin <10.0 g/dL.
    22. Prior treatment with setanaxib or participation in a previous setanaxib clinical trial.
    23. Unstable cardiovascular disease as defined by any of the following:
    a. Unstable angina within 6 months prior to Screening
    b. Myocardial infarction, coronary artery bypass graft surgery, or coronary angioplasty within 6 months prior to Screening
    c. Cerebrovascular accident within 6 months prior to Screening
    d. New York Heart Association Class III or IV heart failure
    24. Presence of any laboratory abnormality or condition that, in the opinion of the Investigator, could interfere with or compromise a patient’s treatment, assessment, or compliance with the protocol and/or study procedures.
    1.Una prueba de embarazo positiva o periodo de lactancia para las pacientes.2.Cualquier acontecimiento histórico o actual de descompensación hepática definido como hemorragia por varices/hipertensión portal y/o encefalopatía hepática, peritonitis bacteriana espontánea, ascitis que requiere tratamiento o inclusión en la lista de trasplantes de hígado.3.Antecedentes de trasplante de hígado, inclusión actual en una lista de trasplantes de hígado o puntuación MELD actual ≥12 a menos que el paciente esté recibiendo tratamiento anticoagulante, o una puntuación Child-Pugh ≥6.4.Cirrosis con complicaciones, lo que incluye antecedentes o presencia de carcinoma hepatocelular.5.Bilirrubina total >2 × LSN. En caso de elevación de la bilirrubina total >LSN, la albúmina sérica de la selección debe estar dentro del intervalo de referencia.Se puede repetir la extracción de muestras de sangre (con análisis por parte del laboratorio central) a criterio del investigador en la visita de selección 2 para los pacientes que cumplan este criterio de exclusión en la visita de selección 1. Si no se cumple este criterio de exclusión en la visita de selección 2, el paciente puede ser apto para el estudio.6.ALT >3 × LSN y/o AST >3 × LSN en plasma.Se puede repetir la extracción de muestras de sangre a criterio del investigador en la visita de selección 2 para los pacientes que cumplan este criterio de exclusión en la visita de selección 1. Si no se cumple este criterio de exclusión en la visita de selección 2, el paciente puede ser apto para el estudio.7.INR >1,2 a menos que el paciente esté recibiendo tratamiento anticoagulante.8.Tasa de filtración glomerular estimada (TFGe) por debajo de 60 ml/min/1,73 m2, calculada por el laboratorio central mediante la ecuación del Grupo Colaborativo de Epidemiología de la Enfermedad Renal Crónica (Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI).9.Tirotropina >LSN en la selección.10.Etiología competitiva de la hepatopatía11.Afecciones médicas que podrían causar elevaciones no hepáticas de la FA.12.Antecedentes conocidos de infección por el VIH. Si la prueba de anticuerpos anti-VIH es positiva, el laboratorio central debe confirmar la negatividad para el ARN del VIH.13.Cirugía o afección médica que pueda afectar significativamente a la absorción de medicamentos.14.Resultado positivo en la prueba de detección de drogas en orina en la selección.15.Pacientes que reciben medicamentos prohibidos en los 3 meses anteriores a la visita de selección 1, incluidos corticoesteroides orales y sistémicos,colchicina, micofenolato de mofetilo, azatioprina, metotrexato, sulfasalazina, leflunomida, ciclofosfamida, valproato, isoniazida o nitrofurantoína. Cualquier agente biológico en las 12 semanas o 5 semividas previas a la selección, lo que sea más largo. En el caso de rituximab, su uso en los 168 días previos a la selección es excluyente. Consulte la lista completa de medicamentos prohibidos en la Sección 6.6.16.Tratamiento con cualquier fármaco en investigación en las 12 semanas previas a la visita de selección 1 o 5 semividas del PEI o inscripción actual en un ensayo clínico intervencionista.17.Indicios de cualquiera de las anomalías de la conducción cardíaca siguientes: Un intervalo QTc según Fredericia de >450 milisegundos en varones o >470 milisegundos en mujeres, calculado por el evaluador central. Se excluirá a los pacientes con bloqueo auriculoventricular de segundo o tercer grado.18.Tratamiento en curso o tratamiento previsto con un marcapasos, un desfibrilador cardioversor implantado u otro dispositivo electrónico implantado.19.Antecedentes de neoplasia maligna en los 5 años anteriores a la selección, con las siguientes excepciones:a.Carcinoma localizado de cuello uterino tratado de forma adecuada.b.Carcinoma basocelular o epidermoide u otro cáncer de piel distinto del melanoma localizado tratado de forma adecuada.20.Aparición de cualquier infección aguda que requiera tratamiento antibiótico sistémico en las 2 semanas previas a la visita de selección 1.21.Antecedentes de trastorno de la médula ósea, incluida anemia aplásica, o cualquier anemia significativa actual definida como un valor de hemoglobina <10,0 g/dl.22.Tratamiento previo con setanaxib o participación en un ensayo clínico previo con setanaxib.23.Enfermedad cardiovascular inestable definida por cualquiera de los siguientes motivos:a.Angina inestable en los 6 meses anteriores a la selección.b.Infarto de miocardio, cirugía de revascularización coronaria o angioplastia coronaria en los 6 meses previos a la selección.c.Accidente cerebrovascular en los 6 meses previos a la selección.d.Insuficiencia cardíaca de clase III o IV según la Asociación de Cardiología de Nueva York.24.Presencia de cualquier anomalía de laboratorio o afección que, en opinión del investigador, pueda interferir o comprometer el tratamiento, la evaluación o el cumplimiento de un paciente con el protocolo o los procedimientos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of patients achieving a biochemical response at Week 52, defined as:
    - Alkaline phosphatase (ALP) reduction to <1.67×upper limit of normal (ULN) and
    - ALP reduction of ≥15% from Baseline and
    - Total bilirubin ≤1×ULN
    Proporción de pacientes que alcanzaron una respuesta bioquímica en la semana 52, definida como:
    - reducción de la fosfatasa alcalina (FA) a <1,67 × límite superior de la normalidad (LSN);
    reducción de la FA ≥15 % con respecto al inicio, y
    bilirrubina total ≤1 × LSN
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week-52
    Semana 52
    E.5.2Secondary end point(s)
    - Change in liver stiffness at Week 52 compared to Baseline, as assessed by transient elastography (FibroScan®)
    - Change in fatigue at Week 52 compared to Baseline, as assessed by the PBC-40 item questionnaire (PBC 40) fatigue domain and the fatigue domain of the Patient Reported Outcomes Measurement Information System (PROMIS) 29 questionnaire
    - Change in pruritus at Week 52 compared to Baseline, as assessed by the PBC-40 itch domain, 5 D itch scale, and Pruritus Visual Analogue Scale (VAS) in patients with pruritus at Baseline
    - Adverse events (AEs). Monitoring for AEs at all visits.
    - AEs of special interest (AESIs):
    Drug induced liver injury (DILI)
    Anemia
    Hypothyroidism
    - Laboratory tests:
    Hematology
    Biochemistry
    Urinalysis
    Thyroid function
    - Vital signs
    - 12-lead electrocardiograms (ECGs): clinically significant abnormalities
    - Cambio en la rigidez hepática en la semana 52 respecto al inicio, evaluada mediante elastografía transitoria (FibroScan®)
    - Cambio en la fatiga en la semana 52 respecto al inicio, evaluado mediante el dominio de fatiga del cuestionario de 40 ítems de CBP (PBC-40) y el dominio de fatiga del cuestionario del sistema de información de medición de resultados notificados por el paciente (PROMIS)-29
    - Cambio en el prurito en la semana 52 respecto al inicio, evaluado mediante el dominio de picor de PBC-40, la escala de picor 5-D y la escala visual analógica (EVA) del prurito en pacientes con prurito al inicio
    - Acontecimientos adversos (AA). Supervisar los AA en todas las visitas.
    - AA de especial interés (AAEI):
    Lesión hepática inducida por fármacos (LHIF)
    Anemia
    Hipotiroidismo
    - Análisis de laboratorio:
    Hematología
    Bioquímica
    Análisis de orina
    Función tiroidea
    - Constantes vitales
    - Electrocardiogramas (ECG) de 12 derivaciones: anomalías clínicamente significativas
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week-52
    Semana 52
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) 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 trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA76
    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
    Canada
    Israel
    New Zealand
    United States
    Austria
    Belgium
    Denmark
    France
    Germany
    Hungary
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    Switzerland
    United Kingdom
    Czechia
    Greece
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last visit or last procedure of the last patient in the study.
    El final del estudio se define como la fecha de la última visita o del último procedimiento del último paciente del estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months11
    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: 254
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 64
    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 state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 318
    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.
    Ninguna
    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 Decision2022-01-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-14
    P. End of Trial
    P.End of Trial StatusOngoing
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