Clinical trial NCT01471028: Assess Safety and Efficacy of ELAD (Extracorporeal Liver Assist System) in Subjects With Alcohol-Induced Liver Failure
Official title: A Randomized, Open-Label, Multicenter, Controlled Study to Assess Safety and Efficacy of ELAD in Subjects With Alcohol-Induced Liver Decompensation (AILD)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Alcoholic Hepatitis
Keywords: Acute alcoholic hepatitis
alcoholic
hepatitis
liver
Lead sponsor: Vital Therapies, Inc.
Sponsor class: INDUSTRY
First posted: 2011-11-11
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival
timeFrame: 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 outcomes:
measure: Number of Survivors at Study Day 91.
timeFrame: Up to Study Day 91.
Other outcomes:
measure: Number of Progression-free Survivors at Study Day 91
timeFrame: Study Day 1 up to Study Day 91
Locations:
city: Phoenix
country: United States
facility: Maricopa Integrated Health System (MIHS)
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Medical Center
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Coronado
country: United States
facility: Sharp Coronado Hospital
state: California
city: Los Angeles
country: United States
facility: Keck Hospital of University of Southern California
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford School of Medicine/Stanford University Medical Center
state: California
city: San Diego
country: United States
facility: University of California San Diego Medical Center - Hillcrest
state: California
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: Piedmont Atlanta Hospital
state: Georgia
city: Atlanta
country: United States
facility: Emory University Hospital
state: Georgia
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota - Twin Cities Campus
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New Brunswick
country: United States
facility: Rutgers University Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Philadelphia
country: United States
facility: Drexel University College of Medicine
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: Methodist Dallas Medical Center
state: Texas
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: San Antonio
country: United States
facility: The University of Texas Health Science Center - Texas Liver Institute
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah Hospital
state: Utah
city: Seattle
country: United States
facility: Swedish Medical Center - Transplant Program
state: Washington
city: Seattle
country: United States
facility: University of Washington - Harborview Medical Center
state: Washington
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: London
country: United Kingdom
facility: King's College Hospital
state: England
city: Hamstead
country: United Kingdom
facility: Royal Free Hospital
state: London
city: Birmingham
country: United Kingdom
facility: University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
state: West Midlands
city: Bristol
country: United Kingdom
facility: United Hospitals Bristol NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
Study officials:
affiliation: Vital Therapies, Inc.
name: Jan Stange, MD
role: STUDY_DIRECTOR
affiliation: PA - Drexel University College of Medicine
name: David J Reich, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: GA - Emory University Hospital
name: Ram Subramanian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - New York University Langone Medical Center
name: Lewis Teperman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - Columbia University Medical Center
name: Robert Brown, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MN - University of Minnesota Medical Center - Twin Cities Campus
name: Julie Thompson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - Montefiore Medical Center
name: Paul Gaglio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Keck Hospital of University of Southern California
name: Linda Sher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - Westchester Medical Center
name: David Wolf, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: TX - Methodist Dallas Medical Center
name: Parvez Mantry, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PA - University of Pittsburgh Medical Center
name: Ali Al-Khafaji, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: WA - Swedish Medical Center - Transplant Program
name: Marquis E Hart, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - North Shore University Hospital
name: David Bernstein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: TX - Baylor University Medical Center
name: Sumeet K Asrini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ - Maricopa Integrated Health System
name: Thomas Ardiles, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: WA - University of Washington - Harborview Medical Center
name: Charles Landis, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: DC - Georgetown University Hospital
name: Rohit Satoskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IL - Rush University Medical Center
name: Nikunj Shah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MS - University of Mississippi Medical Center
name: Brian Borg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: South Australia - Flinders Medical Centre - Bedford Park
name: Alan Wigg, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Western Australia - Sir Charles Gairdner Hospital - Nedlands
name: Gary Jeffrey
role: PRINCIPAL_INVESTIGATOR
affiliation: GA - Piedmont Atlanta Hospital
name: Lance L Stein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: OH - Cleveland Clinic Foundation
name: Talal Adhami, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PA - Albert Einstein Medical Center
name: Simona Rossi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - Bristol - United Hospitals Bristol NHS Foundation Trust
name: Anne McCune, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital
name: Ahmed M Elsharkawy, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AR - University of Arkansas for Medical Sciences
name: Andre Duarte-Rojo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: FL - Tampa General Hospital
name: Angel Alsina, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NJ - Rutgers University Hospital
name: Jag Sunderram, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Australia - Royal Prince Alfred Hospital - New South Wales
name: Geoffrey McCaughan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MA - Beth Israel Deaconess Medical Center
name: Raza Malik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UT - University of Utah Hospital
name: Juan Gallegos-Orozco, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Sharp Coronado Hospital
name: Tarek I Hassanein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AZ - University of Arizona Medical Center
name: Shahid Habib, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MA - Massachusetts General Hospital
name: Winfred W Williams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Cedars-Sinai Medical Center
name: Pedram Enayati, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - England - Cambridge University Hospitals NHS Foundation Trust
name: Michael Allison, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - England - Royal Free Hospital
name: Rajiv Jalan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - University of California San Diego Medical Center - Hillcrest
name: Alexander Kuo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - Scotland - Royal Infirmary of Edinburgh
name: Alasdair Hay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Madrid - Hospital Ramón y Cajal
name: Agustin Albillos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: FL - University of Miami Hospital
name: Kalyan R Bhamidimarri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: FL - Cleveland Clinic Florida
name: Xaralambos (Bobby) Zervos, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Stanford School of Medicine/Stanford University Medical Center
name: Waldo Concepcion, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UK - England - King's College Hospital
name: Julia A Wendon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: TX - The University of Texas Health Science Center - Texas Liver Institute
name: Fred Poordad, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.