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    Summary
    EudraCT Number:2019-004941-34
    Sponsor's Protocol Code Number:GFT505B-319-1
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-06-04
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2019-004941-34
    A.3Full title of the trial
    A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response or Intolerance to Ursodeoxycholic Acid
    Studio in doppio cieco, randomizzato e controllato con placebo con estensione a lungo termine in aperto volto a valutare l'efficacia e la sicurezza di elafibranor 80 mg in pazienti affetti da colangite biliare primitiva con risposta inadeguata o intolleranza all'acido ursodesossicolico
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Double-blind Randomized, Placebo-Controlled Study and Open-label Long Term Extension to Evaluate the Efficacy and Safety of Elafibranor 80 mg in Patients with Primary Biliary Cholangitis with Inadequate Response or Intolerance to Ursodeoxycholic Acid
    Studio in doppio cieco, randomizzato e controllato con placebo con estensione a lungo termine in aperto volto a valutare l'efficacia e la sicurezza di elafibranor 80 mg in pazienti affetti da colangite biliare primitiva con risposta inadeguata o intolleranza all'acido ursodesossicolico
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberGFT505B-319-1
    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
    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
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGENFIT
    B.5.2Functional name of contact pointCarol Addy, MD
    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 number0016179536469
    B.5.6E-mailcarol.addy@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 Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2182
    D.3 Description of the IMP
    D.3.1Product nameElafibranor
    D.3.2Product code [GFT505]
    D.3.4Pharmaceutical form 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.3.9.1CAS number 824932-88-9
    D.3.9.2Current sponsor codeGFT505
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboCoated 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
    colangite biliare primitiva
    E.1.1.1Medical condition in easily understood language
    Primary Biliary Cholangitis
    colangite biliare primitiva
    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 21.0
    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 evaluate the effect of elafibranor (80 mg/day) on cholestasis as defined by the primary endpoint over 52 weeks of the treatment compared to placebo.
    Valutare l'effetto di elafibranor (80 mg/die) sulla colestasi, come definita dall'endpoint primario, in 52 settimane di trattamento rispetto al placebo
    E.2.2Secondary objectives of the trial
    To evaluate the effect of Elafibranor (80 mg/day) on normalisation of alkaline phosphatase (ALP) over 52 weeks of the treatment compared to placebo
    To evaluate the effect of Elafibranor (80 mg/day) on pruritus over 52 weeks of the treatment compared to placebo
    Valutare l'effetto di elafibranor (80 mg/die) sulla normalizzazione della fosfatasi alcalina (ALP) in 52 settimane di trattamento rispetto al placebo
    Valutare l'effetto di elafibranor (80 mg/die) sul prurito in 52 settimane di trattamento rispetto al placebo
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1)Must have provided written informed consent and agree to comply with the study protocol
    2)Males or females age of 18 to 75 years inclusive at first Screening Visit (SV)
    3)PBC diagnosis as demonstrated by the presence of = 2 of the following 3 diagnostic criteria:
    a.History of elevated ALP levels for = 6 months prior to randomization (V1)
    b.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 (ANA)
    c.Liver biopsy consistent with PBC
    4)ALP = 1.67 x ULN (based on two values - see section 3.5.1)
    5)TB = 2 x ULN
    To ensure adequate representation of moderately advanced disease or at risk of progression to clinical outcomes, at least 10% of randomized patients will be moderately advanced per Rotterdam Criteria (TB > ULN or Albumin < LLN) and at least 20% will have a TB > 0.6 x ULN (patients at risk of progression)
    6)Must have at least 4 available values for PBC Worst Itch NRS during each of the 7 day intervals in the 14 days prior to randomization (V1),
    for a total of at least 8 values for PBC Worst Itch NRS in the last 14 days prior to randomization (V1)
    7)UDCA for at least 12 months (stable dose = 3 months) prior to screening, or unable to tolerate UDCA treatment (no UDCA for = 3 months) prior to screening (per country standard-of-care dosing)
    8)If on colchicine must be on a stable dose for = 3 months prior to screening
    9)Medications for management of pruritus (e.g., cholestyramine, rifampin, naltrexone or sertraline) must be on a stable dose for = 3 months prior to screening
    10)Patients taking statins or ezetimibe must be on a stable dose for = 2 months prior to screening
    11)Females participating in this study must be of non-child bearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the last drug intake:
    •Non-child bearing potential: Cessation of menses for at least 12 months due to ovarian failure or surgical sterilization such as bilateral
    oophorectomy, or hysterectomy
    •Highly effective contraception methods include:
    a.Combined (estrogen and progrestogen containing) hormaonal contraception associated with inhibition of ovulation, oral, intravaginal or transdermal
    b.Progestogen-only hormonal contraception associated with inhibition of ovulation, oral, injectable or implantable
    c.Intrauterine device (IUD)
    d.Intrauterine hormoine release system (IUS)
    e.Bilateral tubal occlusion
    f.Vasectomized partner
    g.Sexual abstinence, if required by local IRB/IEC regulations and/or considered adequate by National laws (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient)
    12)For patients who consent to have liver biopsy samples collected, patients in whom it is safe and practical to proceed with a liver biopsy, and who agree to have:
    a.1 liver biopsy during the Screening Period (if no historical biopsy within 6 months before screening is available)
    b.1 liver biopsy after 52-weeks of treatment
    1) Fornitura del consenso informato scritto e volontà di attenersi al protocollo dello studio
    2) Soggetti di sesso maschile o femminile di età compresa tra 18 e 75 anni (inclusi) alla prima visita di screening (VS)
    3) Diagnosi di PBC, come dimostrato dalla presenza di =2 dei seguenti 3 criteri diagnostici:
    a. Anamnesi di livelli elevati di ALP per =6 mesi prima della randomizzazione (V1)
    b. Titoli positivi degli anticorpi anti-mitocondri (AMA) (>1/40 all'immunofluorescenza o M2 positivi tramite saggio immuno-assorbente legato ad un enzima [ELISA]) o positività degli anticorpi antinucleo (ANA) specifici per la PBC
    c. Biopsia epatica in linea con la PBC
    4) ALP =1,67 volte il limite superiore della norma (ULN) (in base a due valori – vedere sezione 3.5.1)
    5) Bilirubina totale (TB) =2 × l'ULN
    Per garantire una adeguata rappresentazione di malattia moderatamente avanzata o pazienti a rischio di progressione ad esiti clinici, almeno il 10% dei pazienti randomizzati soffriranno di malattia moderatamente avanzata secondo i criteri di Rotterdam (TB >ULN o Albumina < limite inferiore della norma [LLN]) e almeno il 20% dei pazienti avranno un valore di TB >0,6 x l'ULN (pazienti a rischio di progressione)
    6) Almeno 4 valori disponibili per la Scala di valutazione numerica (Numeric Rating Scale, NRS) del peggior prurito per la PBC durante ciascuno degli intervalli di 7 giorni nei 14 giorni precedenti alla randomizzazione (V1), per un totale di almeno 8 valori della scala NRS del peggior prurito inclusi negli ultimi 14 giorni prima della randomizzazione (V1)
    7) Trattamento con UDCA da almeno 12 mesi (dose stabile da =3 mesi) prima dello screening o incapacità di tollerare il trattamento con UDCA (UDCA non assunto da =3 mesi) prima dello screening (secondo il trattamento standard di cura del Paese)
    8) In caso di trattamento con colchicina, il paziente deve aver assunto una dose stabile da =3 mesi prima dello screening
    9) I farmaci per la gestione del prurito (ad es. colestiramina, rifampina, naltrexone o sertralina) devono essere somministrati a dose stabile per =3 mesi prima dello screening
    10) I pazienti in trattamento con statine o ezetimibe devono assumere una dose stabile da =2 mesi prima dello screening
    11) Le donne che partecipano a questo studio non devono essere potenzialmente fertili o devono utilizzare metodi anticoncezionali altamente efficaci per l'intera durata dello studio e per 1 mese dopo l'ultima assunzione del farmaco in studio:
    • Le donne sono considerate non potenzialmente fertili se le mestruazioni sono cessate da almeno 12 mesi a causa di insufficienza ovarica o sterilizzazione chirurgica, quali ooforectomia bilaterale o isterectomia
    • I metodi di contraccezione altamente efficaci includono:
    a) Contraccezione ormonale combinata (contenente estrogeni e progestinico) con inibizione di ovulazione, per via orale, intravaginale o transdermica
    b) Contraccezione ormonale a base di solo progestinico associata a inibizione di ovulazione, per via orale, iniettabile o impiantabile
    c) Dispositivo intrauterino (IUD)
    d) Sistema intrauterino a rilascio di ormone (IUS)
    e) Occlusione tubarica bilaterale
    f) Partner sottoposto a vasectomia
    g) Astinenza sessuale, se richiesta dalle disposizioni dei comitati IRB/CEI locali, e/o se considerata adeguata da leggi nazionali (l'affidabilità dell'astinenza sessuale deve essere valutata in relazione alla durata dello studio clinico e allo stile di vita preferito e consueto della paziente)
    12) Per i pazienti che acconsentono a fornire campioni di biopsia epatica, pazienti per cui è sicuro e pratico procedere a una biopsia epatica e che accettano di sottoporsi a:
    • 1 biopsia epatica durante il Periodo di Screening (nel caso in cui non sia disponibile una biopsia d'archivio ottenuta nei 6 mesi che precedono lo screening)
    • 1 biopsia epatica dopo 52 settimane di trattamento
    E.4Principal exclusion criteria
    1)History or presence of other concomitant liver disease including:
    a)Positive anti-hepatitis A virus (HAV) immunoglobulin M (IgM) antibodies or positive hepatitis B surface antigen (HBsAg) or positive anti-hepatitis C virus (HCV) ribonucleic acid (RNA) (tested for in case of
    known cured HCV infection or positive HCV Ab at screening)
    b)Primary sclerosing cholangitis (PSC)
    c)Alcoholic liver disease (ALD)
    d)Autoimmune hepatitis (AIH) or if treated for an overlap of PBC with AIH, or if there is suspicion and evidence of overlap AIH features, that cannot be explained alone by insufficient response to UDCA
    e)Nonalcoholic steatohepatitis (NASH)
    f)Gilbert's Syndrome (exclusion due to interpretability of bilirubin levels)
    g)Known history of alpha-1 antitrypsin deficiency
    2)Clinically significant hepatic decompensation, including:
    a)History of liver transplantation, current placement on a liver transplant list, current Model for End-Stage Liver Disease-Sodium (MELD-Na) score = 12 linked to hepatic impairment
    b)Patients with cirrhosis/portal hypertension complications, including known esophageal varices, 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
    c)Hepatorenal syndrome (type I or II)
    3)Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease) or which may diminish life expectancy to < 2 years,
    including known cancers
    4)Patient has a positive test for Human Immunodeficiency Virus (HIV) Type 1 or 2 at screening, or patient is known to have tested positive for HIV
    5)Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematologic, gastrointestinal, neurological, or psychiatric disease as evaluated by the investigator; other clinically significant medical conditions that are not well controlled
    6)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 screening visit (SV1)
    7)For female patients: known pregnancy, or has a positive serum pregnancy test, or lactating
    8)Administration of the following medications are prohibited as specified below:
    a)2 months prior to screening: fibrates and glitazones
    b)3 months prior to screening: azathioprine, cyclosporine, methotrexate, mycophenolate, pentoxifylline, budesonide and other systemic corticosteroids (parenteral and oral chronic administration only);
    potentially hepatotoxic drugs (including a-methyl-dopa, sodium valproic acid isoniazid, or nitrofurantoin)
    c)12 months prior to screening: antibodies or immunotherapy directed against ILs or other cytokines or chemokines
    d)For patients with previous exposure to OCA, OCA should be discontinued 3 months prior to screening
    9)Patients who are currently participating in, plan to participate in, or have participated in an investigational drug study or medical device study containing active substance within 30 days or five half-lives, whichever is longer, prior to screening; for patients with previous exposure to seladelpar, seladelpar should be discontinued 3 months prior to screening
    10)Patients with previous exposure to elafibranor
    11)SV value ALT and/or AST > 5 x ULN
    12)For patients with AT or TB>ULN at SV1, variability of AT or TB > 40% (see section 3.5.1)
    13)SV value albumin<3.0 g/dl
    14)Severely advanced patients according to Rotterdam criteria (TB >
    ULN and albumin < LLN)
    15)SV value INR > 1.3 due to altered hepatic function
    16)SV value CPK > 2 x ULN
    [...]
    1) Anamnesi o presenza di altre epatopatie concomitanti, tra cui:
    a) Positività agli anticorpi immunoglobuline M (IgM) contro il virus dell'epatite A (HAV) o positività all'antigene di superficie dell'epatite B (HBs Ag) o positività all'acido ribonucleico (RNA) del virus dell'epatite C (HCV) (test eseguito in caso di infezione nota curata da HCV o positività agli anticorpi [Ab] contro l'HCV allo screening)
    b) Colangite sclerosante primitiva (Primary Sclerosing Cholangitis, PSC)
    c) Epatopatia alcolica (Alcoholic Liver Disease, ALD)
    d) Epatite autoimmune (Autoimmune Hepatitis, AIH), trattamento per una sovrapposizione della PBC con l'AIH o sospetto ed evidenza di caratteristiche di AIH sovrapponibili, che non possono essere spiegate solo in base a una risposta insufficiente all'UDCA
    e) Steatoepatite non alcolica (Nonalcoholic steatohepatitis, NASH)
    f) Sindrome di Gilbert (esclusione dovuta all'interpretabilità dei livelli di bilirubina)
    g) Anamnesi nota di deficit di alfa-1 antitripsina
    2) Scompenso epatico clinicamente significativo, tra cui:
    a) Anamnesi di trapianto di fegato, presenza corrente in una lista di attesa per un trapianto di fegato, punteggio attuale =12 al modello per la malattia epatica allo stadio terminale (MELD-Na) collegato alla compromissione epatica
    b) Pazienti con complicazioni da cirrosi/ipertensione portale, ivi inclusi varici esofagee, ascite, anamnesi di emorragie delle varici o interventi associati (ad es. inserimento di bendaggi delle varici o di shunt portosistemico intraepatico transgiugulare [Transjugular Intrahepatic Portosystemic Shunts, TIPS]) ed encefalopatia epatica, anamnesi o presenza di peritonite batterica spontanea, carcinoma epatocellulare
    c) Sindrome epatorenale (tipo I o II)
    3) Condizioni mediche che possono causare aumenti non epatici dell'ALP (ad esempio, la malattia di Paget) o che possono ridurre l'aspettativa di vita a <2 anni, inclusi i tumori noti
    4) Pazienti con risultato positivo al test per il virus dell'immunodeficienza umana (HIV) di tipo 1 o 2 allo screening oppure pazienti sottoposti in passato a test dell'HIV con esito positivo
    Evidenza di qualsiasi altra malattia immunologica, endocrina, ematologica, gastrointestinale, neurologica o psichiatrica secondo la valutazione dello sperimentatore
    5) Altre condizioni clinicamente significative non ben controllate
    6) Anamnesi di abuso di alcol, definito come consumo di più di 30 g di alcol puro al giorno per gli uomini e di più di 20 g di alcol puro al giorno per le donne, o abuso di altre sostanze entro 1 anno prima della visita di screening (VS1)
    7) Per le pazienti di sesso femminile: gravidanza nota o test di gravidanza sul siero positivo o allattamento
    8) La somministrazione dei seguenti farmaci è vietata come specificato di seguito:
    a) 2 mesi prima dello screening: fibrati e glitazoni
    b) 3 mesi prima dello screening: azatioprina, ciclosporina, metotrexato, micofenolato, pentossifillina, budesonide e altri corticosteroidi sistemici (solo somministrazione cronica per via orale e parenterale); farmaci potenzialmente epatotossici (tra cui a-metil-dopa, valproato di sodio, isoniazide o nitrofurantoina)
    c) 12 mesi prima dello screening: anticorpi o immunoterapia mirati alle interleuchine (IL) o altre citochine o chemochine
    d) Nei pazienti con esposizione precedente a OCA, l’OCA dovrebbe essere interrotto 3 mesi prima dello screening
    9) Pazienti attualmente partecipanti o che hanno intenzione di partecipare o che hanno partecipato a uno studio su un farmaco sperimentale o a uno studio su un dispositivo medico contenente un principio attivo entro 30 giorni o cinque emivite prima dello screening, a seconda di quale periodo è più lungo; i pazienti con precedente esposizione a seladelpar dovrebbero interromperne l’assunzione 3 mesi prima dello screening.
    10) Pazienti precedentemente esposti ad elafibranor
    11) Valore dell'alanina aminotransferasi (ALT) e/o aspartato aminotransferasi (AST) >5 x l'ULN alla VS
    [...]
    E.5 End points
    E.5.1Primary end point(s)
    Response to treatment at week 52 defined as ALP < 1.67 x ULN and TB = ULN and ALP decrease = 15%.
    Risposta al trattamento alla Settimana 52, definita come ALP <1,67 x l'ULN e TB =ULN e diminuzione dell'ALP =15%.
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 52
    Settimana 52,
    E.5.2Secondary end point(s)
    Key Secondary Endpoint:
    Response to treatment based on ALP normalization at week 52.
    Change in pruritus from baseline through week 52 on PBC Worst Itch NRS score.
    Other Secondary Endpoints:
    1)Change from baseline in ALP at 4, 13, 26, 39 and 52 weeks
    2)ALP response defined as 10%, 20% and 40% ALP reduction from baseline at week 52
    3)Response to treatment at week 52 according to:
    a)ALP < 1.5x ULN, ALP decrease = 40% and TB = ULN
    b)ALP < 3x ULN, AST <2x ULN and < TB 1 mg/dL (Paris I)
    c)ALP = 1.5x ULN, AST = 1.5x ULN and TB = ULN (Paris II)
    d)TB response rate of 15% change
    e)Normalization of abnormal TB and/or albumin (Rotterdam)
    f)TB = 0.6 x ULN
    g)ALP = 1.67x ULN and TB = 1 mg/dL [1]
    h)No worsening of TB defined as level of TB= ULN at week 52 or no increase from baseline of more than 0.1XULN at week 52
    4)PBC risk scores at week 52: United Kingdom (UK) PBC score [2] and GLOBE score [3]
    5)Response based on bilirubin normalization (TB = ULN) at week 52
    6)Response based on albumin normalization at week 52
    7)Change from baseline to week 52 in hepatobiliary injury and liver function as measured by AST, ALT, gamma-glutamyl transferase (GGT),
    5' NT, total and conjugated bilirubin, albumin, INR and ALP fractionated (hepatic)
    8)Change from baseline to week 52 in biomarkers of inflammation as measured by high-sensitivity C-Reactive Protein (hsCRP), fibrinogen, haptoglobin and tumor necrosis factor-alpha (TNF-alfa)
    9)Change from baseline to week 52 in immune response as measured by immunoglobulin G (IgG) and IgM
    10)Change from baseline to week 52 in biomarkers, and non-invasive measures of hepatic fibrosis as measured by enhanced liver fibrosis (ELF)(HA, PIINP, TIMP-1), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor beta (TGF-ß), cytokeratin-18 (CK-18) (M65 and M30), Pro-C3 and liver stiffness measured by Transient Elastography (TE) (continuous)
    11)Change from baseline to week 52 in lipid parameters as measured by total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), highdensity lipoprotein cholesterol (HDL-C), calculated VLDL-C and TG
    12)Change from baseline to week 52 in fasting plasma glucose (FPG)
    13)Change from baseline to week 52 in bile acids and biomarkers of bile acid synthesis as measured by bile acids, serum 7a-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF-19)
    14)Proportion of patients with no worsening of pruritus from baseline to week 52 as measured by the PBC Worst Itch NRS
    15)Response in PBC Worst Itch NRS defined as at least 30% reduction from baseline of NRS at week 52 in patients with a baseline NRS = 4
    16)Change from baseline to week 52 in 5D-Itch
    17)Change from baseline to week 52 in Patient Reported Outcome Measurement Information System (PROMIS) Fatigue Short Form 7a
    18)Change from baseline to week 52 in the Epworth Sleepiness Scale (ESS)
    19)Change from baseline to week 52 in PBC-40
    20)Change from baseline to week 52 in health utility as measured by the EQ-5D-5L
    21)Change from baseline to week 52 in serum markers of bone turnover and in bone mineral density (hip and lumbar) assessed by DEXA scanning
    22)Onset of clinical outcomes described as a composite endpoint composed of:
    a)MELD-Na >14 for patients with baseline MELD-Na <12
    b)Liver transplant
    c)Uncontrolled ascites requiring treatment
    d)Hospitalization for new onset or recurrence of any of the following:
    i)variceal bleed
    ii)hepatic encephalopathy defined as West-Haven score of 2 or more
    iii)spontaneous bacterial peritonitis
    e)Death
    23)Safety and tolerability as assessed by:
    a)SAE, AE, AESI, physical examination, vital signs, medical history, ECG
    b)Chemistry and hematology
    c)Liver markers
    d)Renal biomarkers (including urinalysis)
    e)Other biochemical safety markers
    24)PK assessments by GFT505 and GF1007 concentrations measurement in plasma
    Endpoint secondari principali:
    Risposta al trattamento sulla base della normalizzazione dell'ALP alla Settimana 52.
    Variazioni nel prurito dal basale alla Settimana 52 secondo il punteggio alla NRS del peggior prurito per la PBC.
    Altri endpoint secondari:
    1) Variazione rispetto al basale dell'ALP dopo 4, 13, 26, 39 e 52 settimane
    2) Risposta dell'ALP, definita come riduzione del 10%, 20% e 40% dell'ALP dal basale alla Settimana 52
    3) Risposta al trattamento alla Settimana 52 in base a:
    a) ALP <1,5 x l'ULN, diminuzione dell'ALP =40% e TB =ULN
    b) ALP <3 x l'ULN, AST <2 x l'ULN e TB <1 mg/dl (Paris I)
    c) ALP =1,5 x l'ULN, AST =1,5 x l'ULN e TB = ULN (Paris II)
    d) Variazione del tasso di risposta della TB pari al 15%
    e) Normalizzazione di livelli anomali di TB e/o albumina (Rotterdam)
    f) TB =0,6 x l'ULN
    g) ALP = 1,67x l'ULN e TB =1 mg/dl [1]
    h) Nessun peggioramento della TB, definito come livello di TB =ULN alla Settimana 52 o assenza di aumento rispetto al basale di più di 0,1 x l'ULN alla Settimana 52
    4) Punteggi di rischio per la PBC alla Settimana 52: punteggio PBC del Regno Unito (UK PBC) [2] e punteggio GLOBE [3]
    5) Risposta basata sulla normalizzazione della bilirubina (TB =ULN) alla Settimana 52
    6) Risposta basata sulla normalizzazione dell'albumina alla Settimana 52
    7) Variazione dal basale alla Settimana 52 della lesione epatobiliare e della funzionalità epatica misurata mediante AST, ALT, gamma glutamil transferasi (GGT), 5’NT, bilirubina totale e coniugata, albumina, INR e ALP frazionata (epatica)
    8) Variazione dal basale alla Settimana 52 dei biomarcatori di infiammazione misurati mediante proteina C reattiva ad alta sensibilità (hsCRP), fibrinogeno, aptoglobina e fattore di necrosi tumorale alfa (TNF-a)
    9) Variazione dal basale alla Settimana 52 della risposta immunitaria, misurata mediante immunoglobuline G (IgG) e IgM
    10) Variazione dal basale alla Settimana 52 dei biomarcatori e di misure non invasive di fibrosi epatica misurata mediante fibrosi epatica avanzata (ELF) (HA, PIINP, TIMP-1), inibitore-1 dell'attivatore del plasminogeno (PAI-1), fattore di crescita trasformante beta (TGF-ß), citocheratina 18 (CK-18) (M65 e M30), Pro-C3 e rigidità epatica misurata mediante elastografia transiente (TE) (continua)
    11) Variazione dal basale alla Settimana 52 dei parametri lipidici misurati mediante colesterolo totale (TC), colesterolo veicolato dalle lipoproteine a bassa densità (LDL-C), colesterolo veicolato dalle lipoproteine ad alta densità (HDL-C), VLDL-C calcolato e TG
    12) Variazione dal basale alla Settimana 52 del glucosio plasmatico a digiuno (FPG)
    13) Variazione dal basale alla Settimana 52 degli acidi biliari e dei biomarcatori della sintesi dell'acido biliare misurati mediante acidi biliari, 7a-idrossi-4-colesten-3-one (C4) nel siero e fattore di crescita dei fibroblasti 19 (FGF-19)
    14) Percentuale di pazienti che non presentano un peggioramento del prurito dal basale alla Settimana 52 sulla base della scala NRS del peggior prurito per la PBC
    15) Risposta alla scala NRS del peggior prurito per la PBC definita come riduzione di almeno il 30% rispetto al basale del punteggio alla NRS alla Settimana 52 in pazienti con un punteggio NRS al basale =4
    16) Variazione dal basale alla Settimana 52 alla scala del prurito a 5 dimensioni (5D-Itch)
    17) Variazione dal basale alla Settimana 52 nel modulo breve 7a relativo all'affaticamento del sistema di informazioni delle misure di esito riportate dal paziente (Patient Reported Outcome Measurement Information System, PROMIS)
    18) Variazione dal basale alla Settimana 52 nella scala di Epworth per la valutazione della sonnolenza (Epworth Sleepiness Scale, ESS)
    19) Variazione dal basale alla Settimana 52 allo strumento PBC-40
    20) Variazione dal basale alla Settimana 52 nell'utilità sanitaria, valutata secondo il punteggio EQ-5D-5L
    [...]
    E.5.2.1Timepoint(s) of evaluation of this end point
    All of the secondary endpoints have defined timepoints included above.
    All of the secondary endpoints have defined timepoints included above.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group 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 trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Canada
    Chile
    Mexico
    South Africa
    Turkey
    United States
    Belgium
    France
    Germany
    Italy
    Spain
    Switzerland
    United Kingdom
    Argentina
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months3
    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: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 Yes
    F.3.3.2Women of child-bearing potential using contraception No
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 150
    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)
    standard of care as per investigator decision.
    standard of care as per investigator decision.
    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 Decision2021-03-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-13
    P. End of Trial
    P.End of Trial StatusOngoing
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