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    Summary
    EudraCT Number:2012-005563-27
    Sponsor's Protocol Code Number:VTI-208
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-06-06
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-005563-27
    A.3Full title of the trial
    A RANDOMIZED, OPEN-LABEL, MULTICENTER, CONTROLLED 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 therapy as a continuous liver support to a subject with compromised liver function owing to alcohol-induced liver decompensation, allowing time for the subject's native liver to regenerate to a healthy state. The primary objective of the study is to evaluate safety and efficacy of ELAD with respect to overall survival (OS) of subjects up to Study Day 91.
    A.4.1Sponsor's protocol code numberVTI-208
    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 organisationVital Therapies Inc., Andrea Loewen-Rodriguez
    B.5.2Functional name of contact pointVP, Regulatory Affairs and QA
    B.5.3 Address:
    B.5.3.1Street Address15010 Avenue of Sciences, Suite 200
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92128
    B.5.3.4CountryUnited States
    B.5.4Telephone number001858673 6840
    B.5.5Fax number001858673 4375
    B.5.6E-mailaloewen@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 IMPHaemodialysis
    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 (r) Human Cell-Based Bio-Artificial Liver Support System
    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
    Alcoholic liver disease
    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 17.0
    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 No
    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) up to Study Day 91, with follow-up protocol VTI-208 providing additioanl survival data up to a maximum of 5 years that wil be inclduded, as available, through VTI-208 study termination (after the last surviving enrolled subject completes study day 91). This will be assessed using a Kaplan-Meier survival analysis of the ITT population utilizing a log-rank test.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to determine the proportion of survivors at Study Days 28 and 91.

    Exploratory objectives are to evaluate the ability of ELAD to stabilize liver function, measured using the MELD-based TTP up to day 91, and the proportion of progression-free survivors (PFS) up to study days 28 and 91. Progression is defined as death or the first observed increase of at least 5 points from End of Study Day 1 MELD score (for both the ELAD and Control groups) until at least 24 hours after the ELAD Treatment Period is ended (end of Day 7 for Controls) and up to both End of Study Days 28 and 91 following Randomization. In the rare case that ELAD therapy is started prior to the End of Study Day 1, the -3 hour laboratory values will be used to calculate the MELD score for that subject to compare the progression to a pre-ELAD value.
    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 years;

    2. Total bilirubin ≥ 8 mg/dL;

    3. A clinical diagnosis of alcohol-induced liver decompensation (AILD), based upon evidence (by lab test, medical history, or family interview) of a clinical judgment of a temporal (6 weeks or less) and causal relationship between use of alcohol and this onset of symptoms;

    4. Subjects meeting inclusion criteria 1 through 3 will be classified as having either:

    a. Severe acute alcoholic hepatitis (AAH), with:
    i. Medical history of alcohol abuse; AND
    ii. Maddrey score of ≥ 32; AND
    iii. AAH documented by either:
    1. Confirmatory liver biopsy, OR
    2. Two or more of the following:
    a. Hepatomegaly,
    b. AST > ALT,
    c. Ascites,
    d. Leukocytosis (WBC count above lab normal at site),
    OR

    b. Alcohol-induced decompensation of chronic liver disease that is not acute alcoholic hepatitis (as defined above), with:
    i. MELD score of 18-35; AND
    ii. Underlying chronic liver disease documented by:

    1. Liver biopsy, AND/OR
    2. Laboratory findings, AND/OR
    3. Medical history;

    5. Not eligible for liver transplant during this hospitalization;

    6. Subject or legally authorized representative must provide Informed Consent;

    7. Subject must be eligible for Standard of Care treatment as defined in the protocol.
    E.4Principal exclusion criteria
    Subjects must NOT meet any of the following exclusion criteria:

    1. Platelet count < 40,000/mm3;
    2. International Normalization Ratio (INR) > 3.5;
    3. MELD Score > 35;
    4. AST > 500 IU/L;
    5. Evidence of infection unresponsive to antibiotics;
    6. Evidence of reduction in total bilirubin of 20% or more in the previous 72 hours, if available. 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);
    7. 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 at maximum vasopressor dose at Screening;
    8. Evidence of active bleeding or of major hemorrhage defined as requiring ≥ 2 units packed red blood cells to maintain a stable hemoglobin occurring within 48 hours of Screening;
    9. Clinical evidence of liver size reduction due to cirrhosis (liver size of craniocaudal diameter [sagittal view] < 10 cm when measured laterally on the mid clavicular line (or equivalent measurement) by ultrasound, or liver volume < 750 cc as determined by CT), unless Investigator interpretation of the clinical evidence indicates liver size of < 10 cm or volume < 750 cc is not considered reduced for the individual subject;
    10. Occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct obstruction;
    11. Evidence by physical exam, history, or laboratory evaluation, of significant concomitant disease with expected 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;
    12. Subject has chronic end-stage renal disease requiring chronic hemodialysis for more than 8 weeks (not classified as hepatorenal syndrome);
    13. Subject has liver disease related to homozygous hemachromotosis, Wilson’s Disease, has non-alcoholic fatty liver disease, or Budd-Chiari Syndrome;
    14. Pregnancy as determined by β-human chorionic gonadotropin (HCG) results, or lactation;
    15. Participation in another investigational drug, biologic, or device study within one month of enrollment, except for observational studies;
    16. Previous liver transplant;
    17. Previous enrollment in the treatment phase of another ELAD trial (e.g. subject is not disqualified from enrollment in VTI-208 if they were screened for VTI-210 but did not qualify for enrollment in the treatment phase of the study and therefore did not receive ELAD or Control treatment);
    18. 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;
    19. Refusal to participate in the VTI-208E follow-up study;
    20. Inability to provide an address for home visits.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival will be assessed using a Kaplan-Meier survival analysis of the ITT population utilizing a log-rank test to evaluate the null hypothesis of equality of survival curves through Study Day 91 with follow-up Protocol VTI-208E providing additional survival data up to a maximum of 5 years that will be included, as available, through VTI-208 study termination (after the last surviving enrolled subject completes study day 91). The model will be stratified by the pre-specified stratified randomization factor. Model-based estimates (and confidence limits) of median survival by treatment group and hazard rates along with the hazard ratio and its confidence limits will be produced. This analysis will also be carried out on the Per-Protocol (PP) population as a sensitivity analysis. In addition, a similar sensitivity analysis for 90-day survival will be carried out using only survival data captured up to the end of study day 91. 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 and define analytical strategies to deal with those differences should their arise.
    E.5.1.1Timepoint(s) of evaluation of this end point
    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) up to Study Day 91.
    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 28 and End of Study Day 91 based on the ITT population. Two-tailed alpha will be set at 0.05. These variables will also be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by the stratified randomization factor to compare the proportion of subjects who have survived at End of Study Day 28 and End of Study Day 91 (28 and 91 days following Randomization, respectively). This analysis will also be carried out on the PP population as a sensitivity analysis. CMH analyses are considered sensitivity analyses to help evaluate consistency across subgroups based on the stratification factor. Two-tailed alpha will be set at 0.05 for each test.
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of Study Day 28 and 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Australia
    Germany
    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 years5
    E.8.9.1In the Member State concerned months4
    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 months0
    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: 180
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 200
    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, VTI-208E, will provide extended follow-up of subjects enrolled in VTI-208 over a period of 5 years to determine incidence of survival, cancer, and liver transplant.
    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 Decision2014-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-05-07
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