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.

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.

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.