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

Acute Alcoholic Hepatitis Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02612428
• Other study ID #: VTL-308
• Status: Terminated
• Phase: Phase 3
• Start date: January 2016
• Est. completion date: September 2018

Study information

• Verified date: January 2019
• Source: Vital Therapies, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 151
• Est. completion date: September 2018
• Est. primary completion date: March 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 49 Years

Eligibility

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 ß-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.

Related Conditions & MeSH terms

• Acute Alcoholic Hepatitis
• Hepatitis, Alcoholic

Intervention

Biological:
• ELAD System
An extracorporeal human hepatic cell-based liver treatment

Other:
• Standard of Care (Control)
Standard medical treatment as defined by the protocol

Locations

Country	Name	City	State
Austria	Medizinische Universität Graz	Graz	Styria
Austria	Medizinische Universität Klinik Für Innere Medizin III	Vienna
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Klinikum Landshut gemeinnuetzige GmbH	Landshut	Bavaria
Germany	Universitätsmedizin Mainz	Mainz
Germany	Universitätsklinikum Münster	Münster
Germany	Universitätsmedizin Rostock	Rostock
Ireland	St. Vincent's University Hospital	Dublin
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario Gregorio Marañón	Madrid
Spain	Hospital Puerta de Hierro Majadahonda	Majadahonda	Madrid
Spain	Hospital Universitario Virgen del Rocío	Sevilla
Spain	Hospital Universitario y Politécnico La Fe	Valencia
Spain	Hospital Clínico Universitario Lozano Blesa	Zaragoza
United Kingdom	Belfast Health and Social Care Trust	Belfast
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Doncaster Royal Infirmary	Doncaster
United Kingdom	Ninewells Hospital and Medical School	Dundee	Scotland
United Kingdom	Glasgow Royal Infirmary	Glasgow	Scotland
United Kingdom	Aintree University Hospital	Liverpool	England
United Kingdom	Royal Free Hospital	London
United Kingdom	Royal London Hospital	London
United Kingdom	Nottingham University Hospital	Nottingham
United States	Emory University Hospital	Atlanta	Georgia
United States	Piedmont Atlanta Hospital	Atlanta	Georgia
United States	Mercy Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	University of Missouri Hospital	Columbia	Missouri
United States	Sharp Coronado Hospital	Coronado	California
United States	The Pennsylvania State University and The Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Schiff Center for Liver Diseases/University of Miami	Miami	Florida
United States	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Rutgers University Hospital	Newark	New Jersey
United States	Stanford University Medical Center	Palo Alto	California
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Drexel University	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Vital Therapies, Inc.

Countries where clinical trial is conducted

United States,  Austria,  Germany,  Ireland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Survivors at Study Day 91	Assess the proportion of survivors at Study Day 91	Up to Study Day 91
Secondary	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

External Links

•   A screening tool for referring physicians to see if a patient may qualify for VTL-308. The referring physician is asked to input pertinent lab values and medical condition to determine whether or not patients may qualify for VTL-308.
•   Company website