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    Summary
    EudraCT Number:2018-004323-37
    Sponsor's Protocol Code Number:PEARL-trial
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-07
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-004323-37
    A.3Full title of the trial
    Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt: a multi-centre randomized, double blind, placebo controlled trial. The PEARL trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt: a multi-centre randomized, double blind, placebo controlled trial. The PEARL trial
    A.3.2Name or abbreviated title of the trial where available
    The PEARL trial
    A.4.1Sponsor's protocol code numberPEARL-trial
    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 SponsorAcademic Medical Centre
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAcademic Medical Centre
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportZonMw
    B.4.2CountryNetherlands
    B.4.1Name of organisation providing supportNorgine B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcademic Medical Centre
    B.5.2Functional name of contact pointLeverresearch
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number0031205668468
    B.5.6E-mailleverresearch@amc.uva.nl
    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 Yes
    D.2.1.1.1Trade name Xifaxan
    D.2.1.1.2Name of the Marketing Authorisation holderNogine B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameXifaxan
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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 Yes
    D.2.1.1.1Trade name Lactulose
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameLactulose
    D.3.4Pharmaceutical form Syrup
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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
    post-TIPS Hepatic Encephalopathy (HE)
    E.1.1.1Medical condition in easily understood language
    Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt placement
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10019660
    E.1.2Term Hepatic encephalopathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10076204
    E.1.2Term Minimal hepatic encephalopathy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10066599
    E.1.2Term Hepatic encephalopathy prophylaxis
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10068826
    E.1.2Term Transjugular intrahepatic portosystemic shunt
    E.1.2System Organ Class 10042613 - Surgical and medical procedures
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the prophylactic administration of lactulose and rifaximin in patients who undergo Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement, to lower the incidence of post-TIPS over hepatic encephalopathy (OHE) within the first three months.
    E.2.2Secondary objectives of the trial
    1. ninety day mortality;
    2. transplant-free survival;
    3. the development of a second episode of OHE within the first three months after TIPS placement;
    4. the development of OHE between three and twelve months after TIPS placement;
    5. the change in PHES and S-ANT1 test during the study: at time-points week 4, week 12 and week 52, compared to baseline;
    6. differences in molecular composition of peripheral / portal blood samples at TIPS placement;
    7. differences in molecular composition of peripheral blood samples at baseline, compared to day 10 post-TIPS, week 4, week 12, and week 52;
    8. quality of life;
    9. and cost-effectiveness.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudy 1, protocol version 1.0, date 13 december 2018:
    Title: The evolution of microbiota composition and microbiota-host interaction after TIPS placement in relation to post-TIPS HE and outcome
    Primary objective of this ancillary study is to assess the effect of TIPS placement on microbiota-host interaction based on the following assessments at baseline, day 10 post-TIPS, month 3 and month 12:
    - 16s rRNA based analysis of microbiota in stool
    - 16s rRNA based analysis of microbiota in saliva
    - Circulating biomarkers for inflammatory, circulatory and endothelial function.

    Secondary objectives are:
    - to assess the relationship between post-TIPS hepatic encephalopathy and microbiota composition.
    - to assess the relationship between post-TIPS hepatic encephalopathy and inflammatory, circulatory and endothelial function respectively.
    - to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and microbiota composition.
    - to assess the relationship between post-TIPS acute decompensation/ACLF or mortality at short (3 months) and long term (< 12 months) and inflammatory, circulatory and endothelial function respectively.

    Substudy 2, protocol version 1.0, date 13 december 2018:
    Characterisation of monocyte activation status and cytokine production in decompensated cirrhosis, alcoholic hepatitis and acute on chronic liver failure.
    Objectives:
    • To compare the activation status, immunological and metabolic function of circulating monocytes/macrophages obtained from patients with alcoholic liver cirrhosis (ALD).
    • Identify the levels of bacterial products, in the portal and systemic blood from patients with ALD.
    • Identify the nature and levels of inflammatory cytokines reaching the liver from the gut in patients with decompensated liver disease undergoing TIPS for intractable ascites
    • To determine the pre and post TIPS immunological factors that may be predictive of encephalopathy following TIPS placement.
    • To determine the activation status, cytokines responses, immunological- and metabolic function by circulating monocytes present in the peripheral blood of patients admitted with acute alcoholic hepatitis and acute- on- chronic liver failure and how these individual responses may correlate with survival.
    • To follow up patients longitudinally and identify a set of parameters and read-outs that can predict patient outcome.
    E.3Principal inclusion criteria
    1. Elective TIPS placement for refractory ascites or recurrent variceal bleeding:
    • Recurrent tense ascites and one or more of the following criteria:
    i. Not responding to the maximal dose of diuretics (400mg spironolactone and 160mg furosemide).
    ii. Kidney insufficiency (Creatinine > 135 umol/L) induced by diuretics.
    iii. Electrolyte disturbances (Sodium < 125 mmol/l, Potassium > 5.5 mmol/l) induced by diuretics.
    iv. Not tolerating higher dose of diuretics (e.g. because of subjective side effects like muscle cramps).
    • Recurrent variceal bleeding, not responsive to treatment with endoscopic band ligation and beta-blockers, with a high risk of failure of endoscopic treatment:
    i. Patients with a variceal bleeding and Child-Pugh C (10-13 points) cirrhosis
    ii. Patients with a variceal bleeding, Child-Pugh B and an active bleeding during endoscopy
    2. Age ≥ 18 years
    3. Confirmed liver cirrhosis as documented by liver biopsy, elastography (e.g. Fibroscan) or combination of usual radiological and biochemical criteria.
    4. Signed informed consent
    1. Electieve TIPS plaatsing voor therapie refractaire ascites of therapie refractaire varicesbloeding:
    • Refractaire ascites en een of meer van de volgende criteria:
    i. Niet reagerend op de maximale dosering diuretica (400mg spironolacton en 160mg furosemide).
    ii. Nierinsufficientie (Kreatinine > 135 umol/L) geinduceerd door diuretica.
    iii. Electrolyten verstoren (Natrium < 125 mmol/L, Kalium > 5.5 mmol/L) geinduceerd door diuretica.
    iv. Niet tolereren van hoge dosering diuretica (b.v. door subjectieve klachten van spierkrampen).
    • Therapie refractaire varices bloedingen, niet reagerend op behandeling met endoscopische band ligatie en beta-blokkers, met een hoog risico op falen van endoscopische behandeling:
    i. Patienten met varices bloeding en Child-Pugh C (10-13 punten) cirrose
    ii. Patienten met varices bloeding, Child-Pugh B en een actieve bloeding tijdens endoscopie
    2. Leeftijd ≥ 18 jaar
    3. Bevestigde levercirrose: gedocumenteerd leverbiopt, Fibroscan of een combinatie van de gebruikelijke radiologische en biochemsiche criteria.
    4. Getekend informed consent formulier
    E.4Principal exclusion criteria
    1. Any absolute contraindications for TIPS placement:
    a. History of hepatic encephalopathy grade II-IV without precipitating factor
    b. Heart failure NYHA ≥ grade 3
    c. Hepatocellular carcinoma (multifocal or large or centrally located)
    d. Systemic infection / sepsis
    e. Severe pulmonary hypertension
    f. Unrelieved bile duct obstruction
    g. Technically not feasible
    h. Poor liver function (MELD score > 20)
    2. Use of ciclosporin
    3. Life-threating variceal bleeding with emergency TIPS placement
    4. Age > 80 years
    5. Non-cirrhotic portal hypertension
    6. Portal vein thrombosis
    7. History of OHE not induced by SBP or gastrointestinal bleed
    8. Current or recent (<3 months) use of rifaximin
    9. Overt neurologic diseases such as Alzheimer’s disease, Parkinson’s disease
    10. Pregnant or breastfeeding women
    11. Patients refusing or unable to sign informed consent
    1. Een absolute contraindicatie voor TIPS plaatsing:
    a. Medische voorgeschiedenis van HE graad II-IV zonder uitlokkende factor
    b. Hartfalen NYHA ≥ graad 3
    c. Hepatocellulair carcinoom (multifocaal of groot of centraal gelegen)
    d. Systemische infectie / sepsis
    e. Ernstige pulmonale hypertensie
    f. Onopgeloste galweg obstructie
    g. Technische niet haalbaar
    h. Slechte leverfunctie (MELD score > 20)
    2. Gebruik van cyclosporine
    3. Levensbedreigende varicesbloeding waarbij direct TIPS plaatsing nodig is
    4. Leeftijd > 80
    5. Non-cirrotische portale hypertensie
    6. Vena portae trombose
    7. Medische voorgeschiedenis van klinisch manifeste HE, niet geinduceerd door SBP of gastrointestinale bloeding
    8. Huidig of recent (<3 maanden) gebruik van rifaximine
    9. Ernstig neurlogische ziekte zoals Alzheimer of Parkinson
    10. Zwanger of borstvoedending gevende vrouw
    11. Patienten die weigeren informed consent te tekenen
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint is the development of OHE within three months after TIPS placement determined by the West Haven criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Three months after TIPS placement.
    E.5.2Secondary end point(s)
    Secondary endpoints are 90 day mortality; development of a second episode of OHE within the first three months; development of OHE in the period between three and twelve months after TIPS placement; development of MHE between TIPS placement and twelve months after placement; the increase of the PHES and ANT-1 score compared to baseline. Difference in the composition of portal blood samples, drawn at TIPS placement. Furthermore, quality of life will be assessed by the Liver Disease Symptom Index 2.0 (LSDI 2.0) and EQ-5D-5L questionnaires.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Quality of life is measured at baseline, three and twelve months after TIPS placement.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 226
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 state171
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 238
    F.4.2.2In the whole clinical trial 238
    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 after end of trial.
    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 Decision2019-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-06
    P. End of Trial
    P.End of Trial StatusOngoing
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