Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)
Condition: Acute Liver Failure; Fulminant Hepatic Failure; Primary Graft Non-Function; Surgically-Induced Liver Failure
MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Failure, Acute
Intervention: ELAD
Intervention description: Continuous treatment with the ELAD System for a minimum of 3 days to a maximum of 10 days. The subject's ultrafiltrated blood is circulated through 4 cartridges, each containing approximately 110 grams of C3A cells (approximately 440 grams total).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 8.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: liver failure; acute liver failure; fulminant hepatic failure; primary graft non-function; surgically-induced liver failure; ELAD; ALF; FHF; PNF

Summary:

      This phase 2 study is developed to evaluate the effect of ELAD on overall survival (OS) in
      subjects with acute liver failure (ALF) compared to matched historical controls.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Weight ≥ 40 kg;

          2. Age ≥ 18;

          3. Diagnosis of ALF attributed to one of the following:

               1. FHF (acute liver failure with no preexisting liver disease, see below);

               2. Primary Graft Non-Function (PNF);

               3. Surgically-Induced Liver Failure (including subjects with small for size liver
                  transplants, living donor liver transplants, and subjects with risk of ALF
                  following liver cancer surgery);

          4. Subjects must not be listed for transplant at the time of Enrollment or, if listed, in
             the opinion of the Investigator are unlikely to be transplanted within 72 hours;

          5. Subject or legally authorized representative must provide Informed Consent for VTI-212
             and the Follow-up Registry VTI-212E.

             Subjects with FHF must meet one of the following criteria:

          6. Known acetaminophen ingestion or diagnostic serum level, and at least one of the
             following:

               1. Prothrombin time (PT) > 100 seconds [International Normalized Ratio (INR) > 6.5],
                  OR

               2. Encephalopathy Grade 3 or 4 AND ARTERIAL AMMONIA >100 umol/liter and at least one
                  of the following:

             i. Arterial pH < 7.30 at ≥ 24 hours after drug ingestion or volume resuscitation; ii.
             Renal failure documented by urine output < 0.5 mL/kg/hr over the preceding 12 hours;
             iii. Creatinine > 2.5 mg/dL; OR

          7. Non-acetaminophen-induced FHF with Encephalopathy Grade 3 or 4 and arterial ammonia
             >100 umol/liter, and at least two of the following:

               1. Viral Hepatitis (other than A, B or C) or drug (non-acetaminophen)-induced FHF

               2. Serum bilirubin > 17 mg/dL

               3. Subject > 40 years old

               4. PT > 50 seconds (INR > 3.5)

               5. Jaundice to encephalopathy time ≥ 7 days

        Exclusion Criteria:

          1. Cerebral Perfusion Pressure ≤40 mm Hg for 1 hour or longer as measured by an
             intracranial pressure (ICP) monitor. (NOTE: In those cases where ICP monitor placement
             cannot be performed prior to study enrollment, this exclusion criterion will not
             apply);

          2. Chronic liver disease (e.g., compensated cirrhosis of any etiology, chronic hepatitis,
             nonalcoholic steatohepatitis, cholestatic liver disease, or metabolic liver disease)
             (NOTE: steatosis is not an exclusion criterion);

          3. Acute clinical symptoms that, in the Investigator's opinion, are likely to result in
             death within 48 hours of enrollment;

          4. Evidence of infection unresponsive to antibiotics (e.g. increased tissue involvement
             relative to initial diagnosis, clinical worsening of symptom) 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
                  Enrollment; OR

               3. Presence of spontaneous bacterial peritonitis during the 2 days prior to
                  Enrollment; OR

               4. Clinical and radiological signs of pneumonia.

          5. Concomitant disease including chronic congestive heart failure, severe vascular
             disease, emphysema, AIDS, cancer (except non-melanoma skin cancer), acute fatty-liver
             disease, hepatitis due to herpes virus or Budd-Chiari syndrome. (NOTE: in the case of
             subjects enrolled due to surgery-induced liver failure (SILF) then the original cause
             for the surgery will not be a criterion for exclusion);

          6. Portal hypertension;

          7. Liver dysfunction due to trauma;

          8. Irreversible brain death;

          9. Platelet count < 30,000/mm3 [NOTE: Subject may be included at the physician's
             discretion if platelet count exceeds 30,000/mm3 at time of initiation of therapy (even
             if the value is following platelet transfusion) and can be managed through the
             administration of blood products]

         10. Cardiovascular sepsis-related organ failure assessment score (SOFA score) >3;

         11. Stroke or intracranial hemorrhage;

         12. Seizures uncontrolled by medication;

         13. Acute myocardial infarction;

         14. Lung disease defined by a partial pressure of oxygen measurement (PaO2) ≤60 mmHg or a
             fraction of inspired oxygen (FiO2) ≥0.6, not corrected by medical management
             [including continuous venovenous hemofiltration (CVVH) if indicated] and ventilation
             with a Positive End Expiratory Pressure (PEEP) of >8cm H2O;

         15. Acute Respiratory Distress Syndrome;

         16. Pregnancy as determined by beta-human chorionic gonadotropin (β-hCG) results;

         17. ≤ 2 weeks postpartum;

         18. 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 VTI-212 clinical trial);

         19. Prior ELAD therapy;

         20. Has a Do Not Resuscitate or a Do Not Intubate (DNR/DNI) directive (or local
             equivalent) or any other Advanced Directive limiting Standard of Care in place (the
             DNR/DNI criterion is not applicable in the UK).