Randomized, Open-Label, Multicenter, Controlled, Pivotal Study to Assess Safety and Efficacy of ELAD in Subjects w/ AILD

A Randomized, Open-Label, Multicenter, Controlled, Pivotal 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 of subjects with a clinical diagnosis of alcohol-induced liver decompensation (AILD) through at least Study Day 91.

The secondary objective is to evaluate the proportion of survivors at Study Day 91 using a chi-squared test.

Study Overview

• Status: Terminated
• Conditions: Acute Alcoholic Hepatitis
• Intervention / Treatment: Biological: ELAD System; Other: Standard of Care (Control)

Detailed Description

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): 151
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Medizinische Universität Klinik Für Innere Medizin III
  • Styria
    • Graz, Styria, Austria, 8036
      • Medizinische Universitat Graz
• Germany
  • Hannover, Germany, D-30625
    • Medizinische Hochschule Hannover
  • Mainz, Germany, 55131
    • Universitätsmedizin Mainz
  • Münster, Germany, D-48149
    • Universitatsklinikum Munster
  • Rostock, Germany, D-18065
    • Universitatsmedizin Rostock
  • Bavaria
    • Landshut, Bavaria, Germany, 84034
      • Klinikum Landshut gemeinnuetzige GmbH
• Ireland
  • Dublin, Ireland, Dublin 4
    • St. Vincent'S University Hospital
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic De Barcelona
  • Madrid, Spain, 28007
    • Hospital Universitario Gregorio Marañon
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46026
    • Hospital Universitario y Politécnico La Fe
  • Zaragoza, Spain, 50009
    • Hospital Clinico Universitario Lozano Blesa
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Puerta de Hierro Majadahonda
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Belfast Health and Social Care Trust
  • Birmingham, United Kingdom, B15 2GW
    • Queen Elizabeth Hospital
  • Doncaster, United Kingdom, DN2 5LT
    • Doncaster Royal Infirmary
  • London, United Kingdom, E1 1BB
    • Royal London Hospital
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham University Hospital
  • England
    • Liverpool, England, United Kingdom, L97AL
      • Aintree University Hospital
  • Scotland
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Ninewells Hospital and Medical School
    • Glasgow, Scotland, United Kingdom, G40SF
      • Glasgow Royal Infirmary
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Coronado, California, United States, 92118
      • Sharp Coronado Hospital
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center
  • Florida
    • Miami, Florida, United States, 33136
      • Schiff Center for Liver Diseases/University of Miami
  • 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
  • Maryland
    • Baltimore, Maryland, United States, 21202
      • Mercy Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07101
      • Rutgers University Hospital
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • The Pennsylvania State University and the Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health system
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 49 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

   1. AILD that is sAAH with no underlying liver disease other than alcoholic liver disease, OR
   2. 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.

Exclusion Criteria:

Subjects must NOT have any of the exclusion criteria to be eligible for the study:

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:

   1. Presence of sepsis or septic shock; OR
   2. Positive blood cultures (bacteremia, fungemia) within 72 hours prior to Randomization; OR
   3. Presence of spontaneous bacterial peritonitis during the 2 days prior to Randomization; OR
   4. 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:

   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 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 hemoglobin 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:

    1. Severe acute or chronic cardiovascular, central nervous system, or pulmonary disease;
    2. Cancer that has metastasized or has not yet been treated;
    3. Severe metabolic abnormalities that have not been corrected (See Section 5.1.3);
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 enrollment, 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 enrollment 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: ELAD System; This group will receive treatment with ELAD plus standard of care therapy.	Biological: ELAD System; An extracorporeal human hepatic cell-based liver treatment; Other Names: ELAD
OTHER: Standard of Care (Control); This group will receive standard of care therapy as defined in the protocol.	Other: Standard of Care (Control); Standard medical treatment as defined by the protocol; Other Names: Standard of Care

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 VTL-308E providing additional survival data up to a maximum of 5 years, that was included as available at the time of database lock (28 Aug 2018).	Up to at least Study Day 91, with protocol VTL-308E providing additional survival data (at 6, 9, 12, 24 months) at the time of database lock (28 August 2018).

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
Number of Subjects With Early Change in Bilirubin Levels at Study Day 7	To estimate the effect of ELAD on the number of subjects achieving a 20% reduction in total bilirubin by Day 7 (ECBL20 Yes)	Up to Study Day 7

Collaborators and Investigators

• Sponsor: Vital Therapies, Inc.
• Investigators: Principal Investigator: Ali Al-Khafaji, MD, PA - University of Pittsburgh Medical Center; Principal Investigator: David Reich, MD, PA - Drexel University; Principal Investigator: Nikolaos Pyrsopoulos, MD, NJ - Rutgers University Hospital; Principal Investigator: Valentin Cuervas-Mons, MD, Spain - Hospital Universitario Puerta de Hierro Majadahonda; Principal Investigator: Julie Thompson, MD, MN - University of Minnesota; Principal Investigator: Peter R Galle, MD, Germany - Universitätsmedizin Mainz; Principal Investigator: Hartmut H.-J. Schmidt, MD, Germany - Universitätsklinikum Münster; Principal Investigator: Kristina Chacko, MD, NY - Montefiore Medical Center; Principal Investigator: Constance Mobley, MD, PhD, TX - Houston Methodist Hospital; Principal Investigator: Stephen Caldwell, MD, VA - University of Virginia Health System; Principal Investigator: Kalyan R Bhamidimarri, MD, FL - Schiff Center for Liver Diseases/University of Miami; Principal Investigator: Manuel Romero-Gomez, MD, Spain - Hospital Universitario Virgen del Rocío; Principal Investigator: Tarek Hassanein, MD, CA - Sharp Coronado Hospital; Principal Investigator: Waldo Concepcion, MD, CA - Stanford University Medical Center; Principal Investigator: Martin Prieto Castillo, MD, Spain - Hospital Universitario y Politécnico La Fe; Principal Investigator: Rafael Bañares, MD, Spain - Hospital Universitario Gregorio Marañón; Principal Investigator: Syed Naqvi, MD, MO - University of Missouri Hospital; Principal Investigator: Matthias Dollinger, MD, PhD, Germany - Klinikum Landshut gemeinnuetzige GmbH; Principal Investigator: Karen Krok, MD, PA - The Pennsylvania State University and The Milton S. Hershey Medical Center; Principal Investigator: Rudolf Stauber, MD, Austria - Medizinische Universität Graz; Principal Investigator: Christian Zauner, MD, Austria - Medizinische Universität Klinik Für Innere Medizin III; Principal Investigator: Georg Lamprecht, MD, Germany - Universitätsmedizin Rostock; Principal Investigator: Paul Thuluvath, MD, MD - Mercy Medical Center; Principal Investigator: Trinidad Serrano Aullo, MD, Spain - Hospital Clínico Universitario Lozano Blesa

Publications and helpful links

Helpful Links

• Company website

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 1, 2016
• Primary Completion (ACTUAL): March 1, 2018
• Study Completion (ACTUAL): September 1, 2018

Study Registration Dates

• First Submitted: November 19, 2015
• First Submitted That Met QC Criteria: November 19, 2015
• First Posted (ESTIMATE): November 23, 2015

Study Record Updates

• Last Update Posted (ACTUAL): January 25, 2019
• Last Update Submitted That Met QC Criteria: January 22, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; Liver Diseases; Hepatitis; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis, Alcoholic
• Other Study ID Numbers: VTL-308