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    Summary
    EudraCT Number:2022-002695-37
    Sponsor's Protocol Code Number:CLIN-60190-453
    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:2023-01-10
    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 number2022-002695-37
    A.3Full title of the trial
    A Phase II, Multicenter, Double-Blind, Randomised, Placebo-Controlled Study and Open-Label Long Term Extension to Evaluate the Safety and Efficacy of Elafibranor in Adult Participants with Primary Sclerosing Cholangitis (PSC)
    Estudio en fase II, multicéntrico, con doble enmascaramiento, aleatorizado, comparado con placebo y de extensión a largo plazo sin enmascaramiento para evaluar la seguridad y la eficacia de elafibranor en participantes adultos con colangitis esclerosante primaria (CEP).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study on safety and efficacy of Elafibranor in Adult Participants with Primary Sclerosing Cholangitis (PSC)
    Estudio sobre la seguridad y la eficacia del elafibranor en participantes adultos con colangitis esclerosante primaria (CEP)
    A.4.1Sponsor's protocol code numberCLIN-60190-453
    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 SponsorIpsen Bioscience, 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 supportIpsen Bioscience, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationICON Clinical Research
    B.5.2Functional name of contact pointClinical Project Management
    B.5.3 Address:
    B.5.3.1Street AddressSouth County Business Park
    B.5.3.2Town/ cityCarmanhall and Leopardstown
    B.5.3.3Post codeDublin 18
    B.5.3.4CountryIreland
    B.5.4Telephone number380506201556
    B.5.6E-mailOleksandr.Rudovskyi@iconplc.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.3.2Product code IPN60190; GFT505
    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 INNElafibranor
    D.3.9.1CAS number 923978-27-2
    D.3.9.2Current sponsor codeIPN60190; GFT505
    D.3.9.4EV Substance CodeSUB187548
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code IPN60190; GFT505
    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 INNElafibranor
    D.3.9.1CAS number 923978-27-2
    D.3.9.2Current sponsor codeIPN60190; GFT505
    D.3.9.4EV Substance CodeSUB187548
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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
    Adults patients with Primary Sclerosing Cholangitis (PSC)
    Pacientes adultos con colangitis esclerosante primaria (CEP)
    E.1.1.1Medical condition in easily understood language
    Primary Sclerosing Cholangitis (PSC) is a progressive liver disease characterised by inflammation and fibrosis of the bile ducts with risk of liver failure.
    La colangitis esclerosante primaria (CEP) es una enfermedad hepática progresiva caracterizada por inflamación y fibrosis de los conductos biliares, con riesgo de insuficiencia hepática.
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10036732
    E.1.2Term Primary sclerosing cholangitis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Objectives for the Double-Blind Period (DBP):
    Primary Objectives:
    To assess the safety and tolerability of daily oral administration of elafibranor 80 mg and 120 mg as compared to placebo in adult participants with PSC after 12 weeks of treatment

    Objectives for the Open-Label Extension Period (OLE):
    Primary Objective:
    To assess the long-term safety and tolerability of daily oral administration of elafibranor up to 120 mg during the OLE
    Objetivos para el periodo con doble enmascaramiento (PDE):
    Objetivos principales:
    Evaluar la seguridad y la tolerabilidad de la administración diaria por vía oral de 80 mg y 120 mg de elafibranor, en comparación con el placebo, en participantes adultos con CEP tras 12 semanas de tratamiento.

    Objetivos para el periodo de prolongación sin enmascaramiento (PSE):
    Objetivo principal:
    Evaluar la seguridad a largo plazo y la tolerabilidad de la administración diaria por vía oral de hasta 120 mg de elafibranor durante la PSE.
    E.2.2Secondary objectives of the trial
    1.To evaluate the effect of daily oral administration of elafibranor 80 mg and 120 mg
    -on markers of cholestasis and hepatobiliary injury as compared to placebo in adult participants with PSC after 12 weeks of treatment
    -as compared to placebo in non-invasive markers of hepatic fibrosis as assessed by liver stiffness measurement by transient elastography (FibroScan®) and serum-based biomarkers of fibrosis and of disease activity in adult participants with PSC after 12 weeks of treatment
    2.To characterise the PK of elafibranor and its metabolite GFT1007 in adult participants with PSC using a Population PK approach, including identification of covariates impacting PK variability
    3.To evaluate the maintenance of efficacy and the long-term effect of daily oral administration of elafibranor up to 120 mg during the OLE on markers of cholestasis and hepatobiliary injury
    1 Evaluar el efecto de la administración diaria por vía oral de 80 mg y 120 mg de elafibranor:
    -en los marcadores de colestasis y lesión hepatobiliar, comparado con placebo, en participantes adultos con CEP tras 12 semanas de tratamiento.

    -comparado con placebo, en los marcadores no invasivos de fibrosis hepática, evaluada por la medición de la rigidez del hígado por elastografía de transición (FibroScan®) y en los biomarcadores séricos de fibrosis y actividad de la enfermedad en participantes adultos con CEP tras 12 semanas de tratamiento.

    2.Caracterizar la FC del elafibranor y de su metabolito GFT1007 en adultos con CEP mediante un método de FC poblacional, incluyendo la identificación de covariables que influyen en la variabilidad FC.
    3.Evaluar el mantenimiento de la eficacia y el efecto a largo plazo de la administración diaria por vía oral de hasta 120 mg de elafibranor durante la PSE en los marcadores de colestasis y lesión hepatobiliar.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female participants must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
    2. Participants with a diagnosis of PSC as demonstrated by the presence of the following, and in the absence of apparent causes of secondary sclerosing cholangitis:
    i) Historical evidence of an elevated ALP >ULN since at least 6 months prior to SV1.
    ii) Cholangiogram (e.g. magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) with features compatible with large duct PSC.
    3. ALP ≥1.5x ULN during screening (with variability ≤30% based on two values). The interval between the two consecutive measurements should beat least 2 weeks (and up to 4 weeks). The baseline value will be the average of all values obtained during screening plus the baseline visit measurement (obtained prior to treatment initiation).
    • If the mean value of both ALP values is ≥1.5x ULN and the variability between values is ≤30%, the participant is eligible (even if one of the two values is <1.5x ULN).
    • In cases where one of the two values is >1.5x ULN, but the mean value is <1.5x ULN, or if the variability between values is >30%, an additional value during screening may be obtained at least 2 weeks (and up to 4 weeks) after the previous measurement during screening.
    • In cases where an additional value is checked, the participant will be eligible if the variability between the second and the third value is ≤30%, and the mean value of all ALP values during screening is ≥1.5x ULN.
    • In cases of ineligibility, the candidate may be subsequently re-screened once at investigator’s discretion, and enrolled if stable qualifying values are demonstrated.
    • All ALP values during screening should be analysed via the central laboratory.
    4. Total bilirubin ≤2.0x ULN at SV1.
    5. Participants taking UDCA who have:
    i) Total daily dose ≤23 mg/kg/day.
    ii) Minimum of 6 months of stable treatment prior to screening period and expected to remain on stable dose through the 12-week DBP.
    iii) Minimum of 3 months off treatment prior to screening period if UDCA was recently discontinued.
    6. For participants with IBD:
    i) Participants with Crohn’s disease must be in remission based on the investigator’s clinical assessment and should be on stable treatment prior to randomisation and during screening.
    ii) Participants with ulcerative colitis must be in remission or have low activity disease as per the judgement of the investigator and should be on stable treatment prior to randomisation and during screening.
    iii) Current treatment for IBD is permitted, if the participant has been well controlled for ≥3 months prior to the screening period and is anticipated to remain on a stable dose of drugs for IBD treatment, including biologics, immunosuppressants, immunomodulators, or systemic corticosteroids. This provision regarding stability of IBD treatment applies to the following, among others:
    • 5-aminosalicylic acid drugs.
    • Azathioprine; 6-mercaptopurine; methotrexate.
    • Budesonide (within recommended doses for management of IBD). In addition to oral formulation, topical application of budesonide (rectal foam or enema) is allowed.
    • Other systemic corticosteroids.
    • Biologics (e.g. anti-tumour necrosis factor or anti-integrin therapies).
    • Other immunosuppressants or immunomodulators used for IBD treatment.
    iv) Participants with IBD should have a colonoscopy performed within one year prior to the screening period showing no evidence of dysplasia or cancer.
    7. Medications for management of pruritus (e.g. cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for ≥3 months prior to the screening period.
    8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    Refer to section 5.1 of the protocol for the rest.
    1. Participantes de ambos sexos de entre 18 y 75 años de edad, inclusive, en el momento de firmar el consentimiento informado.
    2. Participantes con diagnóstico de CEP, demostrada por la presencia de lo siguiente, y en ausencia de causas aparentes de colangitis esclerosante secundaria:
    i) Antecedentes de FA elevada >LSN desde al menos 6 meses antes de la VS1.
    ii) Colangiografía (p. ej., colangiopancreatografía por resonancia magnética [CP RM], colangiopancreatografía retrógrada endoscópica [CPRE], colangiografía transhepática percutánea [CTHP]) con características compatibles con CEP de grandes conductos.
    3. FA ≥1,5 veces el LSN durante la selección (con una variabilidad ≤30 % basada en dos valores). El intervalo entre las dos mediciones consecutivas debe ser de al menos 2 semanas ( y hasta 4 semanas). El valor inicial será el promedio de todos los valores obtenidos durante la selección junto con la medición de la visita basal (obtenido antes del inicio del tratamiento).
    • Si el valor medio de los dos valores de FA es ≥1,5 veces el LSN y la variabilidad entre los valores es ≤30 %, el participante es apto (incluso si uno de los dos valores es <1,5 veces el LSN).
    • En los casos en que uno de los dos valores es >1,5 veces el LSN, pero el valor medio es <1,5 veces el LSN, o si la variabilidad entre los valores es >30 %, se podrá obtener durante la selección un valor adicional al menos 2 semanas ( y hasta 4 semanas) después de la medición previa durante la selección.
    • En los casos en que se comprueba un valor adicional, el participante será apto si la variabilidad entre el segundo y el tercer valor es ≤30 %, y el valor medio de todos los valores de FA durante la selección es ≥1,5 veces el LSN.
    • En casos de no idoneidad, el candidato podrá volver a ser seleccionado una vez posteriormente, a criterio del investigador, e inscribirse si se demuestran unos valores aptos estables.
    • Todos los valores de FA durante la selección deberán analizarse en el laboratorio central.
    4. Bilirrubina total ≤2,0 veces el LSN en la VS1.
    5. Participantes que estén tomando AUDC:
    i) Dosis diaria total ≤23 mg/kg/día.
    ii) Tratamiento estable durante 6 meses con mínimo antes del periodo de selección y previsión de seguir tomando una dosis estable durante el PDE de 12 semanas.
    iii) Sin tratamiento durante 3 meses como mínimo antes del periodo de selección si recientemente se ha suspendido el tratamiento con AUDC.
    6. Para participantes con EII:
    i) Los participantes con enfermedad de Crohn deben estar en remisión, según la evaluación clínica del investigador, y deben seguir un tratamiento estable antes de la aleatorización y durante la selección.
    ii) Los participantes con colitis ulcerosa deben estar en remisión o tener baja actividad de la enfermedad, según el criterio del investigador, y deben seguir en tratamiento estable antes de la aleatorización y durante la selección.
    iii) Se permite seguir el tratamiento actual para la EII, si el participante ha estado bien controlado durante ≥3 meses antes del periodo de selección y se prevé que seguirá tomando una dosis estable de fármacos para el tratamiento de la EII, como biológicos, inmunodepresores, inmunomoduladores o corticoesteroides sistémicos. Esta provisión respecto a la estabilidad del tratamiento de la EII se aplica a los siguientes, entre otros:
    • Fármacos de ácido 5-aminosalicílico.
    • Azatioprina, 6-mercaptopurina, metotrexato.
    • Budesonida (a las dosis recomendadas para el tratamiento de la EII). Además de la formulación oral, se permite la aplicación tópica de budesonida (espuma o enema rectal).
    • Otros corticoesteroides sistémicos.
    • Biológicos (p. ej., tratamientos antifactor de necrosis tumoral o antiintegrina).
    • Otros inmunodepresores o inmunomoduladores utilizados para el tratamiento de la EII.
    iv) Los participantes con EII deben haberse realizado una colonoscopia durante el año previo al periodo de selección que no muestre signos de displasia ni de cáncer.
    7. Los medicamentos para el tratamiento del prurito (p. ej., colestiramina, rifampicina, naltrexona o sertralina) deben tomarse a una dosis estable durante ≥3 meses previos al periodo de selección.
    8. El uso de métodos anticonceptivos por parte de hombres y mujeres debe estar en consonancia con las normativas locales relativas a los métodos anticonceptivos para los participantes en estudios clínicos.
    Consúltese el apartado 5.1 del protocolo para obtener más información.
    E.4Principal exclusion criteria
    1. History or presence of other concomitant chronic liver disease including:
    a) ImmunoglobulinG 4 (IgG4) related sclerosing cholangitis, or IgG4 ≥4x ULN at SV1.
    b) Small duct PSC.
    c) Documented history of secondary sclerosing cholangitis.
    d) Presence of hepatitis B surface antigen (HBsAg) at screening.
    e) Hepatitis C virus (HCV) infection defined by positive anti-HCV antibody and positive HCV ribonucleic acid (RNA) (Note: Participants with positive anti-HCV antibody due to previously treated HCV infection, may be enrolled if a confirmatory HCV RNA is undetectable and sustained viral response has been documented).
    f) PBC or positive anti-mitochondrial antibody.
    g) Alcoholic liver disease.
    h) Autoimmune hepatitis (AIH): Simplified Diagnostic Criteria of the IAIHG ≥6.
    i) Presence of history of PSC-PBC or PSC-AIH overlap syndrome.
    j) NASH.
    k) Known history of alpha-1 antitrypsin deficiency.
    2. Presence of percutaneous drain or bile duct stent at screening or within three months prior to screening.
    3. History of bacterial cholangitis within 60 days prior to the screening period, or participant on antibiotics for prophylaxis of recurrent cholangitis.
    4. History or any current suspicion of cholangiocarcinoma or elevated value of carbohydrate antigen 19-9 (CA19-9) >129 U/mL at SV1.
    5. Alpha-fetoprotein (AFP) >20 ng/mL with 4-phase liver computerised tomography (CT) or magnetic resonance imaging (MRI) suggesting presence of liver cancer.
    6. Participants with cirrhosis who are also classified as Child-Pugh B or C based on the Child-Pugh score. Participants with cirrhosis with Child-Pugh A score are allowed.
    7. History of clinically significant hepatic decompensation, including:
    a) History of liver transplantation, current placement on a liver transplant list, current model for end-stage liver disease (MELD)-Na score ≥12 due to hepatic impairment (MELD-Na will be calculated only when MELD >11).
    b) Evidence of complications of cirrhosis, including hepatic decompensation or evidence of significant portal hypertension complications including presence of ascites requiring treatment; history or presence of spontaneous bacterial peritonitis; presence of hepatic encephalopathy grade 2 or higher per West-Haven criteria; history of oesophageal variceal bleeding or related interventions (e.g. oesophageal variceal banding, or transjugular intrahepatic portosystemic shunt placement).
    c) Hepatorenal syndrome (type I or II).
    8. Presence or history of hepatocellular carcinoma.
    9. Medical conditions that may cause non-hepatic increases in ALP (e.g. Paget’s disease).
    10. Medical conditions that may diminish life expectancy to <2 years, including known cancers.
    11. Participant has a positive test for human immunodeficiency virus (HIV) type 1 or 2 at SV1, or participant is known to have tested positive for HIV.
    12. Evidence of any other unstable or untreated clinically significant immunological, endocrine, neurological, gastrointestinal, haematologic, psychiatric diseases as evaluated by the investigator; other clinically significant conditions that are not well controlled.
    13. Known malignancy or history of malignancy within the last 5 years, with the exception of local, successfully treated basal cell carcinoma or in-situ carcinoma of the uterine cervix.
    14. Administration of the following medications are prohibited as specified below:
    a) 3 months prior to the screening period: fibrates and glitazones.
    b) 3 months prior to the screening period: cyclosporine, mycophenolate, pentoxifylline, and chronic systemic corticosteroids (except as specified in inclusion criteria 6 as part of management of IBD at an ongoing stable dose)).
    c) Obeticholic acid.
    d) 2 months prior to the screening period: systemic antibiotics (e.g. minocycline, vancomycin, metronidazole) for prophylaxis of recurrent cholangitis or for treatment of PSC.
    Refer to section 5.2 of the protocol for additional information.
    1.Antecedentes o presencia de otra hepatopatía crónica simultánea, como:
    a) Colangitis esclerosante relacionada con inmunoglobulina G4 (IgG4) o IgG4 ≥4 veces el LSN en la VS1.
    b) CEP de pequeños conductos.
    c)Antecedentes documentados de colangitis esclerosante secundaria.
    d) Presencia de antígeno de superficie de la hepatitis B (HBsAg) en la selección.
    e) Infección por virus de la hepatitis C (VHC), definida por un resultado positivo de anticuerpos anti-VHC y un resultado positivo de ácido ribonucleico (ARN) del VHC
    f) CBP o resultado positivo de anticuerpos antimitocondriales.
    g) Hepatopatía alcohólica.
    h) Hepatitis autoinmunitaria (HAI): criterios diagnósticos simplificados del IAIHG ≥6.
    i) Antecedentes de CEP-CBP o síndrome de superposición de CEP-HAI.
    j)EHNA.
    k) Antecedentes conocidos de déficit de α-1 antitripsina.
    2.Presencia de drenaje percutáneo o endoprótesis de conductos biliares en la selección o en los 3 meses previos a la selección.
    3.Antecedentes de colangitis bacteriana en los 60 días previos al periodo de selección o participante en tratamiento con antibióticos profilácticos por colangitis recurrente.
    4.Antecedentes o sospecha actual de colangiocarcinoma o valor elevado de antígeno carbohidrato 19-9 (CA19-9) >129 U/ml en la VS1.
    5.α-fetoproteína (AFP) >20 ng/ml con tomografía computarizada (TAC) en cuatro fases o resonancia magnética (RM), lo que indica la presencia de cáncer de hígado.
    6.Participantes con cirrosis que también se clasifican como Child-Pugh B o C según la clasificación de Child-Pugh. Se permite participar a pacientes con cirrosis Child-Pugh A.
    7.Antecedentes de descompensación hepática clínicamente significativa, como:
    a) Antecedentes de trasplante hepático, actualmente en lista de espera para un trasplante hepático, puntuación actual del modelo para hepatopatía en fase terminal (MELD)-Na ≥12 por insuficiencia hepática (la MELD-Na se calculará solo si la MELD >11).
    b)Indicios de complicaciones de cirrosis, como descompensación hepática o indicios de complicaciones significativas de hipertensión portal, como presencia de ascitis que requiere tratamiento; antecedentes o presencia de peritonitis bacteriana espontánea; presencia de encefalopatía hepática de grado 2 o superior según los criterios de West-Haven; antecedentes de sangrado por varices esofágicas o intervenciones relacionadas (p. ej., ligadura de varices esofágicas o colocación de derivación portosistémica intrahepática transyugular).
    c)Síndrome hepatorrenal (de tipo I o II).
    8.Presencia o antecedentes de carcinoma hepatocelular.
    9.Afecciones médicas que podrían causar elevaciones no hepáticas de la FA (p. ej., enfermedad de Paget).
    10.Afecciones médicas que podrían disminuir la esperanza de vida a <2 años, como neoplasias conocidas.
    11.El participante tiene un resultado positivo en la prueba del virus de la inmunodeficiencia humana (VIH) de tipo 1 o 2 en la VS1, o se sabe que el participante ha tenido un resultado positivo contra el VIH.
    12.Indicios de otras enfermedades inestables o no tratadas clínicamente significativas inmunitarias, endocrinas, neurológicas, digestivas, hemáticas o psiquiátricas, según la evaluación del investigador; otras afecciones clínicamente significativas que no estén bien controladas.
    13.Neoplasia maligna conocida o antecedentes de neoplasia maligna en los últimos 5 años, excepto carcinoma basocelular o carcinoma de cuello uterino in situ tratados satisfactoriamente.
    14.Se prohíbe la administración de los siguientes medicamentos, especificados a continuación:
    a)3 meses antes del periodo de selección: fibratos y glitazonas.
    b)3 meses antes del periodo de selección: ciclosporina, micofenolato, pentoxifilina y corticoesteroides sistémicos crónicos (excepto de la forma especificada en el criterio de inclusión 6, como parte del tratamiento de la EII a una dosis estable en curso).
    c)Ácido obeticólico.
    d)2 meses antes del periodo de selección: antibióticos sistémicos (p. ej., minociclina, vancomicina, metronidazol) para la profilaxis de la colangitis recurrente o para el tratamiento de la CEP.
    Consúltese el apartado 5.2 del protocolo para información adicional.
    E.5 End points
    E.5.1Primary end point(s)
    During the 12-week DBP:
    • Number and percentage of participants who experience TEAEs, treatment-related TEAEs, SAEs, and AESIs
    • Number and percentage of participants who develop clinically significant changes from baseline in physical examination findings, vital signs, and ECG
    During the OLE period:
    • Number and percentage of participants who develop clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures
    During the OLE period:
    • Number and percentage of participants who experience TEAEs, treatment-related TEAEs, SAEs, and AESIs
    • Number and percentage of participants who develop
    clinically significant changes from baseline in physical
    examination findings, vital signs and ECG
    • Number and percentage of participants who develop
    clinically significant changes from baseline in haematology, chemistry, liver tests, renal tests (including urinalysis), and other laboratory tests and procedures
    Durante el PDE de 12 semanas:
    • Número y porcentaje de participantes que presentan AADT, AADT relacionados con el tratamiento, AAG y AAEI
    • Número y porcentaje de participantes que presentan cambios clínicamente significativos con respecto al inicio en los resultados de la exploración física, las constantes vitales y el ECG
    Durante el periodo de PSE:
    • Número y porcentaje de participantes que presentan cambios clínicamente significativos con respecto al inicio en hematología, bioquímica, pruebas hepáticas, pruebas renales (incluido el análisis de orina) y otros análisis y procedimientos
    Durante el periodo de PSE:
    • Número y porcentaje de participantes que presentan AADT, AADT relacionados con el tratamiento, AAG y AAEI
    • Número y porcentaje de participantes que presentan cambios clínicamente significativos con respecto al inicio en los resultados de la exploración física, las constantes vitales y el ECG
    • Número y porcentaje de participantes que presentan cambios clínicamente significativos con respecto al inicio en hematología, bioquímica, pruebas hepáticas, pruebas renales (incluido el análisis de orina) y otros análisis y procedimientos
    E.5.1.1Timepoint(s) of evaluation of this end point
    For the DBP: After 12 weeks of treatment
    For the OLE: After the last dose of study intervention
    Para el PDE: Tras 12 semanas de tratamiento
    Para la PSE: tras la última dosis de la intervención del estudio
    E.5.2Secondary end point(s)
    Endpoints for the DBP:
    Secondary end point 1 for secondary objective 1:
    • Relative change from baseline in ALP at Week 12
    • Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 12
    • Absolute change from baseline in ALP at Week 12
    • Number and percentage of participants with ALP: <1.3x ULN and <1.5x ULN at Week 12
    • Number and percentage of participants who normalised ALP at Week 12
    • Change from baseline in ALT, AST, GGT, 5’ nucleotidase, total bilirubin, conjugated bilirubin, albumin and fractionated ALP at Week 12

    Secondary end point 2 for secondary objective 2:
    • Change from baseline in ELF test at Week 12
    • Change from baseline in LSM assessed by FibroScan® at Week 12
    • Change from baseline in other non-invasive hepatic fibrosis serum markers as measured by PAI-1, TGF-β, marker of type V collagen formation (Pro-C5), and marker of type III collagen formation (Pro-C3) at Week 12
    • Change from baseline in FIB-4 and APRI at Week 12
    • Change from baseline in CK-18 (M65 and M30) at Week 12
    For secondary PK:
    Individual PK parameters (during a dosing period of 24 hours) after single administration and at steady state:
    - AUC0-24 (area under the plasma concentration-time
    curve from time 0 to 24 hours)
    - Cmax (maximum (peak) plasma drug concentration)
    - Tmax (time to maximum plasma concentration)
    • Population PK parameters:
    - CL (apparent clearance of drug from plasma)
    - VZ (apparent volume of distribution)
    Endpoints for the OLE:
    • Relative change from baseline in ALP at Week 52 and
    Week 96 of treatment in OLE
    • Number and percentage of participants with ≥40% decrease from baseline in ALP at Week 52 and Week 96 of treatment in OLE
    • Absolute change from baseline in ALP at Week 52 and Week 96 of treatment in OLE
    Criterios de valoración para el PDE:
    Criterio de valoración secundario 1 para el objetivo secundario 1:
    • Cambio relativo con respecto al inicio en la FA en la semana 12
    • Número y porcentaje de participantes con una reducción ≥40 % con respecto al inicio en la FA en la semana 12
    • Cambio absoluto con respecto al inicio en la FA en la semana 12
    • Número y porcentaje de participantes con la FA <1,3 veces el LSN y <1,5 veces el LSN en la semana 12
    • Número y porcentaje de participantes con la FA normalizada en la semana 12
    • Cambio con respecto al inicio en la ALT, la AST, la GGT, la 5’-nucleotidasa, la bilirrubina total, la bilirrubina conjugada, la albúmina y la FA fraccionada en la semana 12

    Criterio de valoración secundario 2 para el objetivo secundario 2:
    • Cambio con respecto al inicio en la prueba de ELF en la semana 12
    • Cambio con respecto al inicio en la LSM evaluada por FibroScan® en la semana 12
    • Cambio con respecto al inicio en otros marcadores séricos de fibrosis hepática no invasivos, como el PAI-1, el TGF-β, el marcador de formación de colágeno de tipo V (Pro-C5) y el marcador de formación de colágeno de tipo III (Pro-C3) en la semana 12
    • Cambio con respecto al inicio en el FIB-4 y el APRI en la semana 12
    • Cambio con respecto al inicio en la CK-18 (M65 y M30) en la semana 12

    Para FC secundarios:
    • Parámetros FC individuales (durante un periodo de administración de 24 horas) tras una administración única y en situación de equilibrio:
    – ABC0-24 (área bajo la curva de concentración plasmática y tiempo desde el momento 0 hasta pasadas 24 horas)
    – Cmáx (concentración plasmática máxima [pico] del fármaco)
    – Tmáx (tiempo hasta la concentración plasmática máxima)
    • Parámetros de FC poblacional:
    – CL (aclaramiento aparente del fármaco del plasma)
    – VZ (volumen aparente de distribución)
    Criterios de valoración para la PSE:
    • Cambio relativo con respecto al inicio en la FA en las semanas 52 y 96 de tratamiento en la PSE
    • Número y porcentaje de participantes con una reducción ≥40 % con respecto al inicio en la FA en las semanas 52 y 96 de tratamiento en la PSE
    • Cambio absoluto con respecto al inicio en la FA en las semanas 52 y 96 de tratamiento en la PSE
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the DBP: At week 12
    For the OLE: At week 52 and week 96
    Para el PDE: En la semana 12
    Para la PSE: En las semanas 52 y 96
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Canada
    United States
    France
    Spain
    Germany
    Italy
    Portugal
    United Kingdom
    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
    Última visita del último paciente
    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 months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months13
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 60
    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 Decision2023-02-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-02-10
    P. End of Trial
    P.End of Trial StatusOngoing
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