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    Summary
    EudraCT Number:2016-003817-80
    Sponsor's Protocol Code Number:GFT505B-216-1
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-03-08
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2016-003817-80
    A.3Full title of the trial
    A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Phase 2 Study to Evaluate the Efficacy and Safety of Elafibranor at Doses of 80 mg and 120mg after 12 Weeks of Treatment in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid
    Estudio en fase II multicéntrico, con doble enmascaramiento, aleatorizado y controlado con placebo para evaluar la eficacia y la seguridad de Elafibranor a dosis de 80 mg y 120 mg después de 12 semanas de tratamiento en pacientes con colangitis biliar primaria (CBP) y una respuesta inadecuada al ácido ursodesoxicólico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 2 Efficacy & Safety Study of Elafibranor in patients with PBC
    Estudio en fase II, de eficacia y seguridad de Elafibranor en pacientes con
    CBP
    A.4.1Sponsor's protocol code numberGFT505B-216-1
    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 SponsorGenfit SA
    B.1.3.4CountryFrance
    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 supportGenfit SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenfit SA
    B.5.2Functional name of contact pointSusan North
    B.5.3 Address:
    B.5.3.1Street AddressParc Eurasanté, 885, Avenue Eugène Avinée
    B.5.3.2Town/ cityLOOS
    B.5.3.3Post code59120
    B.5.3.4CountryFrance
    B.5.4Telephone number1617230-5031
    B.5.6E-mailSusan.North@Genfit.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameElafibranor
    D.3.2Product code 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 824932-88-9
    D.3.9.2Current sponsor codeGFT505
    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.3.1Product nameElafibranor
    D.3.2Product code 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 824932-88-9
    D.3.9.2Current sponsor codeGFT505
    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
    Primary biliary cholangitis
    Colangitis biliar primaria
    E.1.1.1Medical condition in easily understood language
    PBC
    CBP
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10034176
    E.1.2Term PBC
    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
    To compare the effect of daily oral administration of elafibranor 80mg and 120 mg on changes in serum alkaline phosphatase (ALP) to that of placebo in patients with PBC and inadequate response to Ursodeoxycholic acid (UDCA).
    Comparar el efecto de la administración oral diaria de Elafibranor 80 mg y 120 mg sobre la fosfatasa alcalina (FA) sérica en comparación con el placebo en pacientes con CBP y respuesta inadecuada al ácido ursodesoxicólico (UDCA).
    E.2.2Secondary objectives of the trial
    To assess the response to treatment based on composite endpoints:
    o ALP < 1.67 × upper limit of normal (ULN) and total bilirubin within normal limit and > 15% decrease in ALP
    o ALP < 2 × ULN and total bilirubin within normal limit and > 40% decrease in ALP
    • To assess response according to: Paris I, Paris II, Toronto I, Toronto II, UK-PBC risk score
    •To assess response based on the percent of patients who normalized ALP & who normalized albumin
    • To assess response based on the percent of patients who normalized bilirubin
    • To assess the change from baseline in AST, GGT, 5’nucleotidase, total bilirubin, conjugated bilirubin, ALT, albumin, lipid parameters, in bile acids, CDCA, cholic acid, litocholic acid, DCA, C4, FGF1, IgM, 5D-itch scale, PBC 40 QOL and VAS
    • To assess the tolerability & safety of elafibranor in patients with PBC
    • To assess PK of elafibranor 80 & 120 mg and its main metabolite in PBC patients and to explore an exposure-response relationship
    •valuar la respuesta al tratamiento según los criterios de evaluación compuestos:
    oFA < 1,67 × límite superior de la normalidad (LSN) y bilirrubina total dentro del límite normal y descenso > 15 % en la FA
    oFA < 2 × LSN y bilirrubina total dentro del límite normal y descenso > 40 % en la FA
    •Evaluar la respuesta de acuerdo con:
    oLa puntuación del riesgo Paris I, Paris II, Toronto I, Toronto II, UK-PBC
    •Evaluar la respuesta sobre la base del porcentaje de pacientes con FA normalizada
    •Evaluar la respuesta sobre la base del porcentaje de pacientes con albúmina normalizada
    •Evaluar la respuesta sobre la base del porcentaje de pacientes con bilirrubina normalizada
    •Evaluar el cambio respecto al valor inicial en AST, GGT, 5’nucleotidasa, bilirrubina total, bilirrubina conjugada, ALT, albúmina
    •Evaluar el cambio respecto al valor inicial en los parámetros de lípidos
    •Evaluar el cambio respecto al valor inicial en los ácidos biliares: CDCA, ácido
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Must have provided written informed consent (IC)
    2. Males or females 18 to 75 years of age
    3. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 diagnostic factors:
    o History of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit)
    o Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay (ELISA) or positive PBC-specific antinuclear antibodies
    o Liver biopsy consistent with PBC
    4. ALP ≥ 1.67x upper limit of normal (ULN)
    5. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit
    6. Contraception: Females participating in this study must be of non-childbearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment, as described below:
    a) Cessation of menses for at least 12 months due to ovarian failure
    b) Surgical sterilization such as bilateral oopherectomy, hysterectomy, or medically documented ovarian failure
    c) If requested by local IRB regulations and/or National laws, sexual abstinence may be considered adequate (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject)
    d) Using a highly effective non-hormonal method of contraception (bilateral tubal occlusion, vasectomised partner or intra-uterine device)
    e) Double contraception with barrier and highly effective hormonal method of contraception (oral, intravaginal or transdermal combined estrogen and progestogen hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable progestogen-only hormonal contraception associated with inhibition of ovulation or intrauterine hormone-releasing system). The hormonal contraception must be started at least one month prior to randomization.
    7. Must agree to comply with the trial protocol.
    1.Se debe haber proporcionado consentimiento informado (CI) por escrito
    2.Hombres o mujeres de entre 18 y 75 años de edad
    3.Diagnóstico de CBP definitivo o probable según demuestra la presencia de al menos 2 de los 3 siguientes factores de diagnóstico:
    o Antecedentes de concentraciones elevadas de FA durante al menos 6 meses antes del día 0 (visita de aleatorización)
    o Positivo a concentraciones de anticuerpos antimitocondriales (Anti-Mitochondrial Antibodies, AMA) > 1/40 en inmunofluorescencia o positivo a mieloma múltiple mediante enzimoinmunoanálisis de adsorción (enzyme-linked immunosorbent assay, ELISA) o positivo para anticuerpos antinucleares específicos de la CBP
    o Biopsia hepática coherente con CBP
    4.FA ≥ 1,67 x límite superior de la normalidad (LSN)
    5.Tomar UDCA durante al menos 12 meses (dosis estable durante ≥ 6 meses) antes de la visita de selección
    6.Anticoncepción: Las mujeres participantes en este estudio no deben tener capacidad para tener hijos o deben usar anticoncepción de alta eficacia durante todo el estudio y durante 1 mes después del fin del tratamiento, según se describe a continuación:
    a)Cese de la menstruación durante al menos 12 meses debido a una insuficiencia ovárica
    b)Esterilización quirúrgica como ovariectomía bilateral, histerectomía o insuficiencia ovárica documentada médicamente
    c)Si lo requieren las regulaciones del Comité Ético de Investigación Clínica local y/o la legislación nacional, puede considerarse adecuada la abstinencia sexual (la fiabilidad de la abstinencia sexual debe evaluarse en relación con la duración del ensayo clínico y el estilo de vida preferido y habitual del sujeto)
    d)Utilización de un método anticonceptivo no hormonal altamente eficaz (oclusión tubárica bilateral, pareja vasectomizada o dispositivo intrauterino)
    e)Dos métodos anticonceptivos, de barrera y hormonal, de alta eficacia (anticoncepción hormonal con estrógenos y progestágenos combinados por vía oral, intravaginal o transdérmica, asociada con la inhibición de la ovulación; anticoncepción hormonal solo con progestágenos por vía oral, inyectable o implantable, asociada con la inhibición de la ovulación; o sistema de liberación de hormonas intrauterino). La anticoncepción hormonal debe iniciarse al menos un mes antes de la aleatorización.
    7.Debe aceptar cumplir el protocolo del ensayo.
    E.4Principal exclusion criteria
    1. History or presence of other concomitant liver diseases including:
    • Hepatitis B or C virus (HCV, HBV) infection
    • Primary sclerosing cholangitis (PSC)
    • Alcoholic liver disease
    • Definite autoimmune liver disease or overlap hepatitis
    • Nonalcoholic steatohepatitis (NASH)
    • Gilbert's Syndrome (due to interpretability of bilirubin levels)
    • Known history of alpha-1 antitrypsin deficiency
    2. Screening CPK > ULN
    3. Screening ALT or AST > 5 ULN
    4. Screening total bilirubin > 2 ULN
    5. Screening serum creatinine > 1.5 mg/dl
    6. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 60 mL/min/1.73 m2).
    7. Patients with moderate or severe hepatic impairment (defined as Child-Pugh B/C)
    8. Platelet count <150 X 10 3/microliter
    9. Albumin <3.5 g/dL
    10. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
    • History of liver transplantation, current placement on a liver transplant list, or current Model for End Stage Liver Disease (MELD) score ≥ 15
    • Patients with cirrhosis/portal hypertension and complications (or signs and symptoms of cirrhosis/portal hypertension), including known esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related interventions (e.g., insertion of variceal bands or transjugular intrahepatic portosystemic shunts [TIPS]), and hepatic encephalopathy, history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma
    • Hepatorenal syndrome (type I or II) or screening serum creatinine > 2 mg/dL (178 μmol/L)
    11. Administration of the following medications is prohibited as specified below:
    • 2 months preceding screening and throughout the trial (up to the last study visit):: fibrates or obeticholic acid, glitazones
    • 3 months prior to screening and throughout the trial (up to the last study visit) ): azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other systemic corticosteroids; and potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
    • 12 months prior to inclusion visit and throughout the trial (up to the last study visit): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines
    12. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
    13. Known history of human immunodeficiency virus (HIV) infection
    14. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)
    15. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial
    16. Anticipated changes to current medications (that will be continued) during the course of the trial
    17. History of alcohol abuse, defined as consumption of more than 30 g pure alcohol per day for men, and more than 20 g pure alcohol per day for women, or other substance abuse within 1 year prior to Day 0 (randomization visit)
    18. Participation in another trial with an investigational drug, biologic, or medical device using active substance within 30 days prior to screening, or within 5 half lives of the active substance, whichever is longer.
    19. History of noncompliance with medical regimens, or patients who are considered to be potentially unreliable
    20. Mental instability or incompetence, such that the validity of informed consent or compliance with the trial is uncertain
    21. Known hypersensitivity to the investigational product or any of its formulation excipients
    22. Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological, neoplastic, or psychiatric disease.
    1.Antecedentes o presencia de otras enfermedades hepáticas simultáneas, entre ellas:
    •Infección por el virus de la hepatitis B o C (VHC, VHB)
    •Colangitis esclerosante primaria (CEP)
    •Enfermedad hepática alcohólica
    •Enfermedad hepática autoinmunitaria confirmada o síndrome de superposición de la hepatitis
    •Esteatohepatitis no alcohólica (NASH)
    •Síndrome de Gilbert (debido a la interpretabilidad de las concentraciones de bilirrubina)
    •Antecedentes conocidos de deficiencia de la antitripsina alfa 1
    2.CPK en la selección > LSN
    3.ALT o AST en la selección > 5 LSN
    4.Bilirrubina total en la selección > 2 LSN
    5.Creatinina sérica en la selección > 1,5 mg/dl
    6.Enfermedad renal importante, incluidas síndrome nefrítico, insuficiencia renal crónica (definida como pacientes con marcadores de daño renal o filtración glomerular calculada [estimated glomerular filtration rate, eGFR] de menos de 60 ml/min/1,73 m2).
    7.Pacientes con afectación hepática moderada o grave (definida como Child-Pugh B/C)
    8.Recuento de plaquetas < 150 X 103/microlitro
    9.Albúmina < 3,5 g/dl
    10.Presencia de complicaciones clínicas de la CBP o descompensación hepática clínicamente significativa, que incluye:
    •Antecedentes de trasplante de hígado, inclusión actual en una lista para recibir un trasplante de hígado o puntuación actual del Modelo para la enfermedad hepática en fase terminal (Model for End Stage Liver Disease, MELD) ≥ 15
    •Pacientes con cirrosis/hipertensión portal y complicaciones (o signos y síntomas de cirrosis/hipertensión portal), incluidas varices esofágicas conocidas, ascitis mal controlada o resistente a los diuréticos, antecedentes de hemorragias varicosas o intervenciones relacionadas (p. ej., inserción de bandas para varices o derivaciones portosistémicas intrahepáticas transyugulares [transjugular intrahepatic portosystemic shunts, TIPS]), y encefalopatía hepática, antecedentes o presencia de peritonitis bacteriana espontánea, carcinoma hepatocelular
    •Síndrome hepatorrenal (tipo I o II) o creatinina sérica en la selección > 2 mg/dl (178 μmol/l)
    11.La administración de los siguientes medicamentos está prohibida tal como se especifica a continuación:
    •2 meses antes de la selección y a lo largo del ensayo (hasta la última visita del estudio): fibratos o ácido obeticólico, glitazonas
    •3 meses antes de la selección y a lo largo del ensayo (hasta la última visita del estudio): azatioprina, colchicina, ciclosporina, metotrexato, micofenolato de mofetilo, pentoxifilina; budesonida y otros corticosteroides sistémicos; y fármacos potencialmente hepatotóxicos (incluidos alfametildopa, ácido valproico sódico, isoniazida, o nitrofurantoína)
    •12 meses antes de la visita de inclusión y a lo largo del ensayo (hasta la última visita del estudio): anticuerpos o inmunoterapia dirigidos contra las interleucinas u otras citocinas o quimiocinas
    12.Si es una mujer: embarazo conocido o una prueba de embarazo en orina positiva (confirmada mediante una prueba de embarazo en suero positiva) o está amamantando
    13.Antecedentes conocidos de infección por el virus de la inmunodeficiencia humana (VIH)
    14.Afecciones médicas que pueden provocar incrementos no hepáticos de FA (p. ej., enfermedad de Paget)
    15.Otras afecciones médicas clínicamente significativas que no están bien controladas o respecto a las que se espera que cambien las necesidades de medicamentos durante el ensayo
    16.Cambios previstos en los medicamentos actuales (que serán continuados) durante el curso del ensayo
    17.Antecedentes de abuso del alcohol, definido como consumo de más de 30 g de alcohol puro al día para los hombres y más de 20 g de alcohol puro al día para las mujeres, o abuso de otras sustancias en el año previo al día 0 (visita de aleatorización)
    18.Participación en otro ensayo con un fármaco en fase de investigación, producto biológico o dispositivo médico que utilice un principio activo en los 30 días previos a la selección o en el plazo de 5 semividas del principio activo, lo que sea más largo
    19.Antecedentes de incumplimiento de los tratamientos médicos, o pacientes que se consideran potencialmente poco fiables
    20.Inestabilidad mental o incompetencia, de tal forma que la validez del consentimiento informado o el cumplimiento del ensayo resulten dudosos
    21.Hipersensibilidad conocida al producto en fase de investigación o a cualquiera de los excipientes de su formulación
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is to evaluate the efficacy of elafibranor 80 mg or 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo.
    Cambio relativo en la FA sérica respecto al valor inicial hasta el fin del tratamiento en cada grupo de Elafibranor, en comparación con el placebo
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline
    Basal
    E.5.2Secondary end point(s)
    • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 1.67 times ULN and total bilirubin within normal limits and ALP reduction > 15%.
    • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as ALP less than 2 times ULN and total bilirubin within normal limits and ALP reduction > 40%
    • Response rate according to Paris I, Paris II, Toronto I, Toronto II, UK PBC risk score
    • Alkaline phosphatase response rates of 10%, 20% and 40% decrease
    • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized ALP at the end of treatment
    • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized bilirubin at the end of treatment
    • Response rate in elafibranor 80mg and 120 mg and placebo groups with response defined as percent of patients with normalized albumin at the end of treatment
    • Changes from baseline in:
    o Gamma-glutamyl transferase (GGT)
    o Alanine aminotransferase (ALT)
    o Aspartate aminotransferase (AST)
    o 5’nucleotidase
    o Bilirubin (total and conjugated)
    o Albumin
    o total cholesterol, LDL-chol, HDL-Chol, Triglycerides
    o Bile acids : CDCA, cholic acid, litocholic acid, DCA
    o C4, FG19
    o IgM
    o Quality of Life: PBC 40 QOL
    o Pruritus: 5-D Pruritus Questionnaire and Visual Analogue Score (VAS)
    o Biomarkers of inflammation and liver fibrosis: TNF-α, TGF-β, IL-6, CK-18 and lysophosphatidic acid
    • Plasma concentrations of elafibranor and its main metabolite and exposure-response relationship
    • Adverse Events (AEs)
    • Cardiovascular parameters (12-lead ECG, heart rate, blood pressure)
    • Hematology and safety parameters
    •Tasa de respuesta en los grupos de Elafibranor 80 mg y 120 mg y placebo con respuesta definida como FA inferior a 1,67 veces el LSN y bilirrubina total dentro de los límites normales y reducción de la FA > 15 %.
    •Tasa de respuesta en los grupos de Elafibranor 80 mg y 120 mg y placebo con respuesta definida como FA inferior a 2 veces el LSN y bilirrubina total dentro de los límites normales y reducción de la FA > 40 %.
    •Tasa de respuesta de acuerdo con la puntuación del riesgo Paris I, Paris II, Toronto I, Toronto II, UK-PBC
    •Tasas de respuesta de la fosfatasa alcalina de descenso del 10 %, 20 % y 40 %
    •Tasa de respuesta en los grupos de Elafibranor 80 mg y 120 mg y placebo con respuesta definida como porcentaje de pacientes con FA normalizada en el fin del tratamiento
    •Tasa de respuesta en los grupos de Elafibranor 80 mg y 120 mg y placebo con respuesta definida como porcentaje de pacientes con bilirrubina normalizada en el fin del tratamiento
    •Tasa de respuesta en los grupos de Elafibranor 80 mg y 120 mg y placebo con respuesta definida como porcentaje de pacientes con albúmina normalizada en el fin del tratamiento
    •Cambios con respecto a los valores iniciales en:
    oGammaglutamil transferasa (GGT)
    oAlanina aminotransferasa (ALT)
    oAspartato aminotransferasa (AST)
    o5’nucleotidasa
    oBilirrubina (total y conjugada)
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 12
    Semana 12
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Germany
    Spain
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    End of Trial is deemed as 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 years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 21
    F.4.2.2In the whole clinical trial 45
    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)
    Patients will return to normal standard of care
    Los pacientes van a retomar el tratamiento habitual.
    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 Decision2017-05-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-31
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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