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    Summary
    EudraCT Number:2015-004529-14
    Sponsor's Protocol Code Number:VTL-308
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-10-07
    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 ConcernedAustria - BASG
    A.2EudraCT number2015-004529-14
    A.3Full title of the trial
    A Randomized, Open-label, Multicenter, Controlled, Pivotal Study to Assess Safety and Efficacy of ELAD® in Subjects with Alcohol-Induced Liver Decompensation (AILD).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study examines the safety and efficacy of using ELAD treatment as continuous liver support in subjects with liver failure secondary to acute hepatocellular insult with a temporal and causal relationship to alcohol, allowing time for the subject's native liver to recover and be restored to a functional state. The primary objective of the study is to evaluate the safety and efficacy of ELAD with respect to overall survival (OS) of subjects through at least Study Day 91.
    A.4.1Sponsor's protocol code numberVTL-308
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02612428
    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 SponsorVital Therapies, 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 supportVital Therapies, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRobert A. Ashley, Vital Therapies, Inc.
    B.5.2Functional name of contact pointEVP & Chief Technical Officer
    B.5.3 Address:
    B.5.3.1Street Address15010 Avenue of Science, Suite 200
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92128
    B.5.3.4CountryUnited States
    B.5.4Telephone number001520289 3236
    B.5.6E-mailrashley@vitaltherapies.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/3/13/1143
    D.3 Description of the IMP
    D.3.1Product nameELAD
    D.3.2Product code ELAD SYSTEM
    D.3.4Pharmaceutical form Living tissue equivalent
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPExtracorporeal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman C3A hepatoblastoma cells
    D.3.9.3Other descriptive nameELAD® Human Hepatic Cell-Based Liver Treatment
    D.3.10 Strength
    D.3.10.1Concentration unit Other
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    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) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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) Yes
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Yes
    D.3.11.3.5.1CAT classification and reference numberELAD falls within the definition of somatic cell therapy medicinal product and can further be considered a combined ATMP. EMA/CAT/345680/2010 & EMA/463750/2010.
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alcohol-Induced Liver Decompensation (AILD)
    E.1.1.1Medical condition in easily understood language
    Alcohol-Induced Liver Decompensation (AILD)
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10019755
    E.1.2Term Hepatitis chronic active
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate safety and efficacy of ELAD® with respect to overall survival (OS) of subjects with a clinical
    diagnosis of alcohol-induced liver decompensation (AILD) through at
    least Study Day 91, with follow-up Protocol VTL-308E providing
    additional survival data up to a maximum of 5 years that will be
    included, as available, through VTL-308 study termination (after the last
    surviving enrolled subject completes Study Day 91). The primary
    objective will be assessed using a Kaplan-Meier survival analysis of the
    Intent-to-Treat (ITT) population utilizing a log-rank test.
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate the proportion of survivors at Study Day 91 using a chi-squared test.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet ALL inclusion criteria to be eligible for the study:
    1. Age ≥ 18;

    2. Total bilirubin ≥16 mg/dL (≥273.6 μmol/L);

    3. A clinical diagnosis of alcohol-induced liver decompensation (AILD),
    based upon lab test or medical history or family interview with a causal
    relationship and temporal association (6 weeks or less) of alcohol use
    and hospital admission for this episode of AILD;

    4. Maddrey score ≥32;

    5. Subjects must have AILD that is severe acute alcoholic hepatitis(sAAH) diagnosed with either:
    a. A confirmatory liver biopsy, OR
    b. Two or more of the following:

    i. Hepatomegaly,
    ii. AST > ALT,
    iii. Ascites,
    iv. Leukocytosis (WBC count above lab normal at site);

    Note: Subjects will be classified as either:
    a. AILD that is sAAH with no underlying liver disease other than
    alcoholic liver disease, OR
    b. AILD that is sAAH with evidence of underlying liver disease other
    than alcoholic liver disease which must be documented by:
    i. Liver biopsy, AND/OR
    ii. Laboratory findings, AND/OR
    iii. Medical history;

    6. Not eligible for liver transplant during this hospitalization;

    7. Subject or legally-authorized representative must provide Informed
    Consent;

    8. Subject must be eligible for Standard of Care treatment as defined in
    the protocol.
    E.4Principal exclusion criteria
    Subjects must NOT have any of the following exclusion criteria:
    1. Age ≥50;

    2. Platelet count <40,000/mm3;

    3. International Normalization Ratio (INR) >2.5;

    4. Serum Creatinine ≥1.3 mg/dL (≥115.04 μmol/L);

    5. MELD score ≥30;

    6. AST >500 IU/L;

    7. Evidence of infection unresponsive to antibiotics (e.g. increased tissue involvement relative to initial diagnosis, clinical worsening of symptoms, etc.) indicated by any of the following:
    a. Presence of sepsis or septic shock; OR
    b. Positive blood cultures (bacteremia, fungemia) within 72 hours prior
    to Randomization; OR
    c. Presence of spontaneous bacterial peritonitis during the 2 days prior
    to Randomization; OR
    d. Clinical and radiological signs of pneumonia;

    8. Evidence of reduction in total bilirubin of 20% or more in the previous 72 hours. Bilirubin measurements must be taken at least 12 hours after any procedure known to artificially alter serum bilirubin (e.g., administration of packed red blood cells, plasma exchange);

    9. Evidence of hemodynamic instability as defined by the following:
    a. Systolic blood pressure <90 mmHg with evidence of diminished
    perfusion unresponsive to fluid resuscitation and/or low-dose pressor
    support; OR
    b. Mean arterial pressure (MAP) <60 mmHg with evidence of
    diminished perfusion unresponsive to fluid resuscitation and/or low-dose pressor support; OR
    c. Requirement for escalating doses of vasopressor support prior to
    Screening; OR
    d. Subject on vasopressors, including but not limited to those listed
    below, at doses above the following at Screening or Randomization:
    • Dobutamine: 5.0 μg/kg/min
    • Dopamine: 2.0 μg/kg/min
    • Norepinephrine: 0.02 μg/kg/min
    • Phenylephrine: 1.0 μg/kg/min
    • Vasopressin: 0.02 U/min

    10. Evidence of active bleeding, major hemorrhage defined as requiring
    ≥2 units packed red blood cells to maintain a stable haemoglobin
    occurring within 48 hours prior to Randomization, or with banding of
    gastroesophageal varices during the 7 days immediately preceding
    screening;

    11. Clinical evidence of liver size reduction due to cirrhosis [liver size of
    the craniocaudal diameter (sagittal view) <10 cm when measured on the mid clavicular line (or equivalent measurement) by ultrasound, or liver volume <1200 cc as determined by CT or MRI], unless Investigator
    interpretation of the clinical evidence indicates liver size of <10 cm or
    volume <1200 cc is not considered reduced for the individual subject,
    and Sponsor agrees;

    12. Occlusive portal vein thrombosis impairing hepatopetal flow, or
    evidence of bile duct obstruction;

    13. Evidence by physical exam, history, or laboratory evaluation, of
    significant concomitant disease with a life expectancy of less than 3
    months, including, but not limited to:
    a. Severe acute or chronic cardiovascular, central nervous system, or
    pulmonary disease;
    b. Cancer that has metastasized or has not yet been treated;
    c. Severe metabolic abnormalities that have not been corrected;

    14. Subject has chronic end-stage renal disease requiring chronic
    hemodialysis for more than 8 weeks (not classified as hepatorenal
    syndrome);

    15. Subject ventilated or intubated;

    16. Subject on hemodialysis;

    17. Subject has liver disease related to homozygous hemachromotosis,
    Wilson's disease, has non alcoholic fatty liver disease, or Budd-Chiari
    Syndrome;

    18. Serological evidence (including viral titers) of active viral hepatitis A,
    B or C infection. If the investigator suspects that the subject may be at
    risk for viral hepatitis A, B or C, and no serology is available, then
    serologies MUST be obtained prior to Randomization, as a positive
    serology would be exclusionary;

    19. Pregnancy as determined by serum β-human chorionic gonadotropin (HCG) results, or subjects of child-bearing potential not willing to use effective means of contraception, without history of medical or surgical sterilization;

    20. Participation in another investigational drug, biologic, or device
    study within one month of enrolment, except for observational studies
    (the observational study setting should not affect the safety and/or
    efficacy of the VTL-308 clinical trial);

    21. Previous liver transplant;

    22. Previous enrolment in the treatment phase of another ELAD trial;

    23. Have a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive
    (or such local equivalent) or any other Advanced Directive limiting
    Standard of Care in place (the DNR/DNI criterion is not applicable in
    Europe);

    24. Refusal to participate in the VTL-308E follow-up study;

    25. Inability to provide an address for home visits.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival (OS) will be assessed using a Kaplan-Meier survival
    analysis of the intent-to-treat (ITT) population utilizing a log-rank test,
    with follow-up Protocol VTL-308E providing additional survival data up
    to a maximum of 5 years that will be included, as available, through VTL-308 study termination. Model-based estimates and confidence limits will be calculated for median survival by treatment group and the hazard ratio and its confidence limits. This analysis will also be carried out on the mITT, Per-Protocol (PP) and Safety populations as sensitivity analyses. Two-tailed alpha for the log-rank test will be set at 0.05. The statistical analysis plan will outline the methods used to account for missing data in this and all other analyses.
    The statistical analysis plan will also evaluate differences in standard of
    care between the groups that may affect subject outcome, such as
    differences in the administration of steroid therapy, and define analytical strategies to deal with those differences should they arise.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After all enrolled subjects either complete Study Day 91, are lost to
    follow up or withdraw consent, or die before that Study Day.
    E.5.2Secondary end point(s)
    A chi-square test will be used to evaluate the proportion of subjects who survived at End of Study Day 91 based on the ITT population. Two-tailed alpha will be set at 0.05. This analysis will also be carried out on the mITT, PP and Safety populations as sensitivity analyses.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of Study Day 91.
    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 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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Standard of care treatment for AILD (as defined in the protocol)
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Austria
    Germany
    Ireland
    Spain
    United Kingdom
    United States
    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
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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: 150
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Due to the critical nature of the subject's condition, they may not be able to understand or execute the informed consent at the time of screening.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    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)
    In addition, an extension of this study, VTL-308E, will provide extended follow-up of subjects enrolled in VTL-308 over a period of 5 years to determine incidence of survival, cancer, liver transplant and quality of life.
    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 Decision2016-12-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-11-10
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-09-14
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