Clinical trial NCT02612428: Randomized, Open-Label, Multicenter, Controlled, Pivotal Study to Assess Safety and Efficacy of ELAD in Subjects w/ AILD
Official title: A Randomized, Open-Label, Multicenter, Controlled, Pivotal Study to Assess Safety and Efficacy of ELAD in Subjects With Alcohol-Induced Liver Decompensation (AILD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Alcoholic Hepatitis
Lead sponsor: Vital Therapies, Inc.
Sponsor class: INDUSTRY
First posted: 2015-11-23
Enrollment: 151
Sex: ALL
Minimum age (years): 18
Maximum age (years): 49
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival
timeFrame: 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 outcomes:
measure: Number of Survivors at Study Day 91
timeFrame: Up to Study Day 91
measure: Number of Subjects With Early Change in Bilirubin Levels at Study Day 7
timeFrame: Up to Study Day 7
Other outcomes:
Locations:
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: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Miami
country: United States
facility: Schiff Center for Liver Diseases/University of Miami
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: Baltimore
country: United States
facility: Mercy Medical Center
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri Hospital
state: Missouri
city: Newark
country: United States
facility: Rutgers University Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Hershey
country: United States
facility: The Pennsylvania State University and The Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel University
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: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Graz
country: Austria
facility: Medizinische Universität Graz
state: Styria
city: Vienna
country: Austria
facility: Medizinische Universität Klinik Für Innere Medizin III
city: Landshut
country: Germany
facility: Klinikum Landshut gemeinnuetzige GmbH
state: Bavaria
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Mainz
country: Germany
facility: Universitätsmedizin Mainz
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Dublin
country: Ireland
facility: St. Vincent's University Hospital
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro Majadahonda
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañón
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital Universitario y Politécnico La Fe
city: Zaragoza
country: Spain
facility: Hospital Clínico Universitario Lozano Blesa
city: Liverpool
country: United Kingdom
facility: Aintree University Hospital
state: England
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
state: Scotland
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: Scotland
city: Belfast
country: United Kingdom
facility: Belfast Health and Social Care Trust
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Doncaster
country: United Kingdom
facility: Doncaster Royal Infirmary
city: London
country: United Kingdom
facility: Royal London Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospital
Study officials:
affiliation: Vital Therapies, Inc.
name: Jan Stange, MD
role: STUDY_DIRECTOR
affiliation: PA - Drexel University
name: David Reich, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: GA - Piedmont Atlanta Hospital
name: Lance Stein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NJ - Rutgers University Hospital
name: Nikolaos Pyrsopoulos, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Universitario Puerta de Hierro Majadahonda
name: Valentin Cuervas-Mons, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MA - Beth Israel Deaconess Medical Center
name: Raza Malik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IL - Rush University Medical Center
name: Nikunj Shah, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PA - Albert Einstein Medical Center
name: Simona Rossi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Clinic de Barcelona
name: Juan Caballeria, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: GA - Emory University Hospital
name: Ram Subramanian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AR - University of Arkansas for Medical Sciences
name: Andres Duarte-Rojo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MN - University of Minnesota
name: Julie Thompson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germany - Universitätsmedizin Mainz
name: Peter R Galle, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germany - Universitätsklinikum Münster
name: Hartmut H.-J. Schmidt, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germany - Medizinische Hochschule Hannover
name: Markus Busch, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NY - Montefiore Medical Center
name: Kristina Chacko, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: OH - Cleveland Clinic Foundation
name: Talal Adhami, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: TX - Houston Methodist Hospital
name: Constance Mobley, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: WI - Aurora St. Luke's Medical Center
name: David J Kramer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: VA - University of Virginia Health System
name: Stephen Caldwell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PA - University of Pittsburgh Medical Center
name: Ali Al-Khafaji, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: FL - Schiff Center for Liver Diseases/University of Miami
name: Kalyan R Bhamidimarri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Universitario Virgen del Rocío
name: Manuel Romero-Gomez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Sharp Coronado Hospital
name: Tarek Hassanein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: CA - Stanford University Medical Center
name: Waldo Concepcion, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Universitario y Politécnico La Fe
name: Martin Prieto Castillo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Universitario Gregorio Marañón
name: Rafael Bañares, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MO - University of Missouri Hospital
name: Syed Naqvi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germany - Klinikum Landshut gemeinnuetzige GmbH
name: Matthias Dollinger, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: PA - The Pennsylvania State University and The Milton S. Hershey Medical Center
name: Karen Krok, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Austria - Medizinische Universität Graz
name: Rudolf Stauber, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Austria - Medizinische Universität Klinik Für Innere Medizin III
name: Christian Zauner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Germany - Universitätsmedizin Rostock
name: Georg Lamprecht, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: MD - Mercy Medical Center
name: Paul Thuluvath, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Spain - Hospital Clínico Universitario Lozano Blesa
name: Trinidad Serrano Aullo, MD
role: PRINCIPAL_INVESTIGATOR
References: