Assess Safety and Efficacy of ELAD (Extracorporeal Liver Assist System) in Subjects With Alcohol-Induced Liver Failure

A Randomized, Open-Label, Multicenter, Controlled Study to Assess Safety and Efficacy of ELAD in Subjects With Alcohol-Induced Liver Decompensation (AILD)

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 at least 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).

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 Model for End Stage Liver Disease (MELD)-based time to progression (TTP) up to Study 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.

Study Overview

• Status: Completed
• Conditions: Acute Alcoholic Hepatitis
• Intervention / Treatment: Biological: ELAD treatment; Other: Standard of care (Control)

Detailed Description

Subjects randomized to the ELAD® group will receive treatment with ELAD® for a maximum of five (5) 24 hour periods as well as standard of care treatment.

Subjects randomized to the Control group will receive standard of care treatment throughout the study.

The ITT population includes all randomized subjects assigned to the group to which they were randomized, irrespective of actual treatment administered. Participant, Baseline Characteristics, and Outcome Measures used the ITT population. The safety population is defined as all subjects who are randomized based on actual treatment received. All serious adverse events and all non-serious adverse events analyses used the safety population.

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Flinders Medical Centre
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
• Spain
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
• United Kingdom
  • Bristol, United Kingdom, BS2 8HW
    • United Hospitals Bristol NHS Foundation Trust
  • Cambridge, United Kingdom, CB20QQ
    • Cambridge University Hospitals NHS Foundation Trust
  • Edinburgh, United Kingdom, EH16 4SA
    • Royal Infirmary of Edinburgh
  • England
    • London, England, United Kingdom, SE5 9RS
      • King's College Hospital
  • London
    • Hamstead, London, United Kingdom, NW3 2QG
      • Royal Free Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B152TH
      • University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Maricopa Integrated Health System (MIHS)
    • Tucson, Arizona, United States, 85724
      • University of Arizona Medical Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Coronado, California, United States, 92118
      • Sharp Coronado Hospital
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90033
      • Keck Hospital of University of Southern California
    • Palo Alto, California, United States, 94304
      • Stanford School of Medicine/Stanford University Medical Center
    • San Diego, California, United States, 92103
      • University of California San Diego Medical Center - Hillcrest
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Hospital
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital
    • Atlanta, Georgia, United States, 30309
      • Piedmont Atlanta Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota - Twin Cities Campus
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers University Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Pittsburgh, Pennsylvania, United States, 15216
      • University of Pittsburgh Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75203
      • Methodist Dallas Medical Center
    • San Antonio, Texas, United States, 78215
      • The University of Texas Health Science Center - Texas Liver Institute
  • Utah
    • Salt Lake City, Utah, United States, 84108
      • University of Utah Hospital
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington - Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • Swedish Medical Center - Transplant Program

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age ≥ 18 years;
• Total bilirubin ≥ 8 mg/dL;
• 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;

• 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:

  1. Hepatomegaly,
  2. AST > ALT,
  3. Ascites,
  4. 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;
• Not eligible for liver transplant during this hospitalization;
• Subject or legally authorized representative must provide Informed Consent;
• Subject must be eligible for Standard of Care treatment as defined in the protocol.

Exclusion Criteria:

• Platelet count < 40,000/mm3;
• International Normalization Ratio (INR) > 3.5;
• MELD Score > 35;
• AST > 500 IU/L;
• Evidence of infection unresponsive to antibiotics;
• 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);

• Evidence of hemodynamic instability as defined by the following:

  1. Systolic blood pressure < 90 mmHg with evidence of diminished perfusion unresponsive to fluid resuscitation and/or low-dose pressor support; OR
  2. Mean arterial pressure (MAP) < 60 mmHg with evidence of diminished perfusion unresponsive to fluid resuscitation and/or low-dose pressor support; OR
  3. Requirement for escalating doses of vasopressor support prior to Screening; OR
  4. Subject at maximum vasopressor dose at Screening;
• Evidence of active bleeding or of major hemorrhage defined as requiring ≥ 2 units packed red blood cells to maintain stable hemoglobin occurring within 48 hours of Screening;
• 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 < 750 cc is not considered reduced for the individual subject;
• Occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct obstruction;

• 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:

  1. Severe acute or chronic cardiovascular, central nervous system, or pulmonary disease;
  2. Cancer that has metastasized or has not yet been treated;
• Subject has chronic end-stage renal disease requiring chronic hemodialysis for more than 8 weeks (not classified as hepatorenal syndrome);
• Subject has liver disease related to homozygous hemachromatosis, Wilson's Disease, has non-alcoholic fatty liver disease, or Budd-Chiari Syndrome;
• Pregnancy as determined by β-human chorionic gonadotropin (HCG) results, or lactation;
• 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 safety and/or efficacy of the VTI-208 clinical trial);
• Previous liver transplant;
• Previous enrollment in the treatment phase of another ELAD trial (e.g. a 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;
• 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 the UK);
• Refusal to participate in the VTI-208E follow-up study;
• Inability to provide an address for home visits.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ELAD Treatment; This group will receive treatment with ELAD plus standard of care treatment.	Biological: ELAD treatment; ELAD treatment consists of treatment with an extracorporeal liver assist system.; Other Names: ELAD
OTHER: Standard of care (Control); This group will receive standard of care treatment as defined in the protocol.	Other: Standard of care (Control); Control receives standard medical treatment.; Other Names: Standard of care as defined by the protocol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The primary endpoint of the study was a comparison of overall survival (OS) between the ELAD-treated and Control groups, with protocol VTI-208E providing additional survival data up to a maximum of 5 years, that was included as available at the time of database lock (31 July 2015).	Up to at least Study Day 91, with protocol VTI-208E providing additional survival data (at 6, 9, 12, 24 months) at the time of database lock (31 July 2015)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Survivors at Study Day 91.	Assess the proportion of survivors at Study Day 91.	Up to Study Day 91.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Progression-free Survivors at Study Day 91	An exploratory objective is to evaluate the ability of ELAD® to stabilize liver function, measured using the MELD-based time to progression (TTP), with progression 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.	Study Day 1 up to Study Day 91

Collaborators and Investigators

• Sponsor: Vital Therapies, Inc.
• Investigators: Principal Investigator: Lewis Teperman, MD, NY - New York University Langone Medical Center; Principal Investigator: Robert Brown, MD, NY - Columbia University Medical Center; Principal Investigator: Paul Gaglio, MD, NY - Montefiore Medical Center; Principal Investigator: Linda Sher, MD, CA - Keck Hospital of University of Southern California; Principal Investigator: David Wolf, MD, NY - Westchester Medical Center; Principal Investigator: Parvez Mantry, MD, TX - Methodist Dallas Medical Center; Principal Investigator: Ali Al-Khafaji, MD, PA - University of Pittsburgh Medical Center; Principal Investigator: Marquis E Hart, MD, WA - Swedish Medical Center - Transplant Program; Principal Investigator: David Bernstein, MD, NY - North Shore University Hospital; Principal Investigator: Sumeet K Asrini, MD, TX - Baylor University Medical Center; Principal Investigator: Thomas Ardiles, MD, AZ - Maricopa Integrated Health System; Principal Investigator: Charles Landis, MD, WA - University of Washington - Harborview Medical Center; Principal Investigator: Brian Borg, MD, MS - University of Mississippi Medical Center; Principal Investigator: Alan Wigg, MD, South Australia - Flinders Medical Centre - Bedford Park; Principal Investigator: Gary Jeffrey, Western Australia - Sir Charles Gairdner Hospital - Nedlands; Principal Investigator: Lance L Stein, MD, GA - Piedmont Atlanta Hospital; Principal Investigator: Anne McCune, MD, UK - Bristol - United Hospitals Bristol NHS Foundation Trust; Principal Investigator: Ahmed M Elsharkawy, MD, UK - University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital; Principal Investigator: Andre Duarte-Rojo, MD, AR - University of Arkansas for Medical Sciences; Principal Investigator: Jag Sunderram, MD, NJ - Rutgers University Hospital; Principal Investigator: Geoffrey McCaughan, MD, Australia - Royal Prince Alfred Hospital - New South Wales; Principal Investigator: Juan Gallegos-Orozco, MD, UT - University of Utah Hospital; Principal Investigator: Tarek I Hassanein, MD, CA - Sharp Coronado Hospital; Principal Investigator: Shahid Habib, MD, AZ - University of Arizona Medical Center; Principal Investigator: Winfred W Williams, MD, MA - Massachusetts General Hospital; Principal Investigator: Pedram Enayati, MD, CA - Cedars-Sinai Medical Center; Principal Investigator: Michael Allison, MD, UK - England - Cambridge University Hospitals NHS Foundation Trust; Principal Investigator: Rajiv Jalan, MD, UK - England - Royal Free Hospital; Principal Investigator: Alexander Kuo, MD, CA - University of California San Diego Medical Center - Hillcrest; Principal Investigator: Alasdair Hay, MD, UK - Scotland - Royal Infirmary of Edinburgh; Principal Investigator: Agustin Albillos, MD, Spain - Madrid - Hospital Ramón y Cajal; Principal Investigator: Xaralambos (Bobby) Zervos, DO, FL - Cleveland Clinic Florida; Principal Investigator: Waldo Concepcion, MD, CA - Stanford School of Medicine/Stanford University Medical Center; Principal Investigator: Julia A Wendon, MD, UK - England - King's College Hospital; Principal Investigator: Fred Poordad, MD, TX - The University of Texas Health Science Center - Texas Liver Institute

Publications and helpful links

General Publications

• Thompson J, Jones N, Al-Khafaji A, Malik S, Reich D, Munoz S, MacNicholas R, Hassanein T, Teperman L, Stein L, Duarte-Rojo A, Malik R, Adhami T, Asrani S, Shah N, Gaglio P, Duddempudi A, Borg B, Jalan R, Brown R, Patton H, Satoskar R, Rossi S, Parikh A, ElSharkawy A, Mantry P, Sher L, Wolf D, Hart M, Landis C, Wigg A, Habib S, McCaughan G, Colquhoun S, Henry A, Bedard P, Landeen L, Millis M, Ashley R, Frank W, Henry A, Stange J, Subramanian R; VTI-208 Study Group. Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial. Liver Transpl. 2018 Mar;24(3):380-393. doi: 10.1002/lt.24986.

Helpful Links

• Vital Therapies, Inc. website

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): August 1, 2015

Study Registration Dates

• First Submitted: November 7, 2011
• First Submitted That Met QC Criteria: November 10, 2011
• First Posted (ESTIMATE): November 11, 2011

Study Record Updates

• Last Update Posted (ACTUAL): February 15, 2019
• Last Update Submitted That Met QC Criteria: January 22, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: liver; hepatitis; alcoholic; Acute alcoholic hepatitis
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Liver Diseases; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis, Alcoholic
• Other Study ID Numbers: VTI-208