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    Summary
    EudraCT Number:2013-001884-21
    Sponsor's Protocol Code Number:VTI-210
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-07-08
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2013-001884-21
    A.3Full title of the trial
    A RANDOMIZED, OPEN-LABEL, MULTICENTER, CONTROLLED STUDY TO ASSESS SAFETY AND EFFICACY OF ELAD IN SUBJECTS WITH SEVERE ACUTE ALCOHOLIC HEPATITIS (sAAH) WHO HAVE FAILED STEROID THERAPY
    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 in subjects with compromised liver function owing to severe acute alcoholic hepatitis (sAAH), 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 through VTI-210 study termination (after the last surviving enrolled subject completes study day 91)
    A.4.1Sponsor's protocol code numberVTI-210
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01829347
    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 organisationAndrea Loewen-Rodriguez, Vital Therapies Inc.
    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 number0018586736840
    B.5.5Fax number0018586734375
    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® 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
    Severe Acute Alcoholic Hepatitis (sAAH)
    E.1.1.1Medical condition in easily understood language
    Severe Acute Alcoholic Hepatitis (sAAH)
    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 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) at Study Day 91 in subjects with a clinical diagnosis of severe acute alcoholic hepatitis (sAAH) who have failed steroid therapy. Folow-up protocol VTI-210E will provide additonal survival data up to a maximum of 5 yeas that will be included, as available, through VTI-210 study termination (after all enrolled subjects complete study day 91, are lost to follow-up or withdraw consent, or die before the study day). The primary objective will be assessed using a Kaplan-Meier survival analysis of the intent-to-treat (ITT) population utilizing a log-rank test to evaluate the null hypthesis of equality of survival curves
    E.2.2Secondary objectives of the trial
    Secondary objectives are to evaluate the proportion of survivors (ITT population) at Study Days 28 and 91 using the chi-square 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 ≥ 8 mg/dL;

    3. Medical history of alcohol abuse with evidence of causal and temporal (<6weeks) relationship to the use of alcohol and the onset of symptoms;

    4. Maddrey score of ≥ 32;

    5. A clinical diagnosis of severe acute alcoholic hepatitis (sAAH) defined asmeeting two or more of the following:
    a. Hepatomegaly
    b. AST > ALT
    c. Ascites
    d. Leukocytosis (WBC count above lab normal at site);

    6. Subject must have either:
    a. a liver biopsy that, in the investigator's opinion, confirms a diagnosis of sAAH (stratum A)
    OR
    b. in the investigator's opinion, a liver biopsy is not justified due to the risk versus the diagnosis value, and no confirmatory liver biopsy is available, in which case the clinical diagnosis is sufficient (stratum B);

    7. Subject must have failed steroid therapy according to the Lille protocol (Lille score >0.45) after completing 7 days of steroids;

    8. Subject must be eligible for Standard of Care treatment as defined in the protocol;

    9. Subject or legally authorized representative must provide Informed Consent for all phases of the study (Treatment, and 5-year Follow-Up Registry);
    E.4Principal exclusion criteria
    Subjects must NOT meet any of the following exclusion criteria:
    1. Platelet count < 50,000/mm3;
    2. International Normalization Ratio (INR) > 3.0;
    3. MELD score > 35;
    4. Evidence of infection unresponsive to antibiotics (e.g. increased tissue involvement relative to initial diagnosis, clinical worsening of symptom, 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;
    5. Evidence of more than one steroid regimen during this episode of liver failure;
    6. Hospital admission for any other episodes of liver decompensation within the past 2 months;
    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 or Randomization (low doses are allowed);
    low dose vasopressor doses are defined as:
    • Dobutamine: Low doses: 2.5 to 5.0 mcg/kg/min
    • Dopamine: Low doses: 0.5 to 2 mcg/kg/min
    • Norepinephrine: Low doses: 0.01 to 0.02 mcg/kg/min
    • Phenylephrine: Low doses: 0.05 to 1 mcg/kg/min
    • Vasopressin: Low doses: 0.01 to 0.02 U/min
    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. Evidence of occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct obstruction;
    10. 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;
    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 < 750 cc as determined by CT], unless Investigator interpretation of the clinical evidence indicates liver size of < 10 cm or volume < 750cc is not considered reduced for the individual subject;
    12. Chronic end-stage renal disease requiring chronic hemodialysis for more than 8 weeks (not classified as hepatorenal syndrome);
    13. Uncontrolled seizures;
    14. Positive serologies for viral hepatitis B (HBsAg) or hepatitis C indicating acute/chronic infection or a positive viral load for either hepatitis B or C;
    15. Pregnancy as determined by β-human chorionic gonadotropin (HCG) results;
    16. Participation in another investigational drug, biologic, or device study within one month of
    enrollment, except for observational studies (the observational study setting should not affect the safety and/or efficacy of the VTI-210 clinical trial);
    17. Currently listed or scheduled for liver transplant during the 90-day study period;
    18. Previous liver transplant;
    19. Previous participation in an ELAD clinical trial as either ELAD or Control subject;
    20. Has a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive (or local equivalent) or any other Advanced Directive limiting Standard of Care in place;
    21. Refusal to participate in the VTI-210E follow-up study;
    22. Is unable to provide an address for follow-up 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 ITT population utilizing a log-rank test to evaluate the null hypothesis of equality of survival curves, with follow-up Protocol VTI-210E providing additional survival data up to a maximum of 5 years that will be included, as available, through VTI-210 study termination (after all enrolled subjects either complete Study Day 91, are lost to follow up or withdraw consent, or die before that Study Day). The model will be stratified by whether or not the clinical diagnosis of sAAH was confirmed with a liver biopsy. Model-based estimates and confidence limits will be calculated for median survival by treatment group and hazard rates along with the hazard ratio and its confidence limits. This analysis will also be carried out on the per-protocol (PP) population as a sensitivity analysis. In addition, a similar sensitivity analysis for Overall 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 define the ITT and PP populations and to account for missing data in this and all other analyses.
    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 28 and End of Study Day 91 based on the ITT population. These analyses will also be performed using a Cochran-Mantel-
    Haenszel (CMH) test stratified by whether or not the clinical diagnosis of sAAH was confirmed with a liver biopsy to compare the proportion of subjects who have survived at End of Study Day 28 and End of Study Day 91 respectively.
    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
    The secondary objectives are to evaluate the proportion of survivors at Study Days 28 and 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 AAH (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 EEA25
    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 years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months7
    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: 135
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 15
    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 state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 90
    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, VTI-210E, will provide extended follow-up of subjects enrolled in VTI-208 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
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation National Institute for Health Research, Clinical Research Network
    G.4.3.4Network Country United Kingdom
    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 Opinion2014-11-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2015-08-21
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