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Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)

Primary Purpose

Acute Liver Failure, Fulminant Hepatic Failure, Primary Graft Non-Function

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ELAD
Sponsored by
Vital Therapies, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Liver Failure focused on measuring liver failure, acute liver failure, fulminant hepatic failure, primary graft non-function, surgically-induced liver failure, ELAD, ALF, FHF, PNF

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Keck Hospital of USC
  • Georgetown University Hospital
  • University of Miami Hospital
  • Tampa General Hospital
  • Cleveland Clinic Floriday
  • Piedmont Atlanta Hospital
  • Emory University Hospital
  • Rush University Medical Center
  • Massachusetts General Hospital
  • University of Minnesota Medical Center - Twin Cities Campus
  • Rutgers University Hospital
  • Montefiore Medical Center
  • New York University Medical Center
  • Cleveland Clinic Foundation
  • Drexel University College of Medicine
  • Methodist Dallas Medical Center - The Liver Institute
  • University of Utah
  • Swedish Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

ELAD plus standard of care

Arm Description

Continuous ELAD treatment for a minimum of 3 days to a maximum of 10 days in addition to a standard of care for subjects with acute liver failure.

Outcomes

Primary Outcome Measures

Overall Survival (OS) of ALF Subjects

Secondary Outcome Measures

Number of Subjects Who Survived at the End of Study Day 28 or Who Received Orthotopic Liver Transplantation on or Before That Study Day.

Full Information

First Posted
June 5, 2013
Last Updated
January 22, 2019
Sponsor
Vital Therapies, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01875874
Brief Title
Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)
Official Title
An Open-Label, Multicenter, Historically-Controlled Study to Assess Safety and Efficacy of ELAD in Subjects With Acute Liver Failure (ALF)
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Terminated
Why Stopped
Due to VTI-208 results, the ELAD clinical plan is being re-evaluated.
Study Start Date
October 2014 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vital Therapies, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed Description
The VTI-212 study (VTI-212) is an open-label, multicenter, historically-controlled study of subjects with acute liver failure (ALF). Approximately 40 subjects who meet the eligibility requirements of the study will receive ELAD treatment in addition to standard of care treatment for ALF. The outcomes of these subjects will be compared with matched historical controls drawn from existing databases. Subjects will undergo ELAD treatment for a minimum of 3 days (72 hours). It is recommended ELAD treatment be continued up to 10 days (240 hours). Following ELAD treatment, subjects will continue standard medical therapy as defined by the institution and be followed through Study Day 28. Subjects' diagnosis of ALF will be attributed to one of the following: Fulminant Hepatic Failure (FHF) (acute liver failure with no preexisting liver disease); Primary Graft Non-Function (PNF); 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. Screening evaluations and assessments will be completed for subjects and reviewed against inclusion/exclusion criteria. Enrollment will define the time of study entry (Hour 0, Study Day 1, study baseline) and inclusion in the Intent-to-treat (ITT) population. Subjects will be evaluated throughout the 28-day study period. If standard medical therapy, as defined by the institution and this protocol is consistent with discharging the subject home, then the subject should be discharged. Prior to discharge, the subject will be advised to attend all follow-up visits. An extension of this study, the VTI-212E study (VTI-212E), will provide additional ELAD survival data, as available, through VTI-212 study termination (after the last surviving enrolled ELAD subject completes Study Day 28). This registry protocol segment of VTI-212 extends the safety monitoring period to 5 years to assess survival, incidence and characterization of tumor (in particular hepatocellular tumor), incidence of liver transplant, and assess quality of life using a standard, validated questionnaire. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Liver Failure, Fulminant Hepatic Failure, Primary Graft Non-Function, Surgically-Induced Liver Failure
Keywords
liver failure, acute liver failure, fulminant hepatic failure, primary graft non-function, surgically-induced liver failure, ELAD, ALF, FHF, PNF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
8 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ELAD plus standard of care
Arm Type
Experimental
Arm Description
Continuous ELAD treatment for a minimum of 3 days to a maximum of 10 days in addition to a standard of care for subjects with acute liver failure.
Intervention Type
Biological
Intervention Name(s)
ELAD
Other Intervention Name(s)
Human Cell-Based Bio-Artificial Liver Support System
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).
Primary Outcome Measure Information:
Title
Overall Survival (OS) of ALF Subjects
Time Frame
Study Day 1 through Study Day 28
Secondary Outcome Measure Information:
Title
Number of Subjects Who Survived at the End of Study Day 28 or Who Received Orthotopic Liver Transplantation on or Before That Study Day.
Time Frame
Study Day 1 through Study Day 28

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Weight ≥ 40 kg; Age ≥ 18; Diagnosis of ALF attributed to one of the following: FHF (acute liver failure with no preexisting liver disease, see below); Primary Graft Non-Function (PNF); 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); 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; 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: Known acetaminophen ingestion or diagnostic serum level, and at least one of the following: Prothrombin time (PT) > 100 seconds [International Normalized Ratio (INR) > 6.5], OR 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 Non-acetaminophen-induced FHF with Encephalopathy Grade 3 or 4 and arterial ammonia >100 umol/liter, and at least two of the following: Viral Hepatitis (other than A, B or C) or drug (non-acetaminophen)-induced FHF Serum bilirubin > 17 mg/dL Subject > 40 years old PT > 50 seconds (INR > 3.5) Jaundice to encephalopathy time ≥ 7 days Exclusion Criteria: 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); 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); Acute clinical symptoms that, in the Investigator's opinion, are likely to result in death within 48 hours of enrollment; 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: Presence of sepsis or septic shock; OR Positive blood cultures (bacteremia, fungemia) within 72 hours prior to Enrollment; OR Presence of spontaneous bacterial peritonitis during the 2 days prior to Enrollment; OR Clinical and radiological signs of pneumonia. 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); Portal hypertension; Liver dysfunction due to trauma; Irreversible brain death; 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] Cardiovascular sepsis-related organ failure assessment score (SOFA score) >3; Stroke or intracranial hemorrhage; Seizures uncontrolled by medication; Acute myocardial infarction; 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; Acute Respiratory Distress Syndrome; Pregnancy as determined by beta-human chorionic gonadotropin (β-hCG) results; ≤ 2 weeks postpartum; 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); Prior ELAD therapy; 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan Stange, MD, Ph.D.
Organizational Affiliation
Vital Therapies, Inc.
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Parvez Mantry, MD
Organizational Affiliation
TX - Methodist Dallas Medical Center - The Liver Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
David J Reich, MD
Organizational Affiliation
PA - Drexel University College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul J Gaglio, MD
Organizational Affiliation
NY - Montefiore Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Juan Gallegos-Orozco, MD
Organizational Affiliation
UT - University of Utah
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Angel Alsina, MD
Organizational Affiliation
FL - Tampa General Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lewis W Teperman, MD
Organizational Affiliation
NY - New York University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nikunj Shah, MD
Organizational Affiliation
IL - Rush University Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Julie Thompson, MD
Organizational Affiliation
MN - University of Minnesota Medical Center - Twin Cities Campus
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Winfred W Williams, Jr., MD
Organizational Affiliation
MA - Massachusetts General Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lance Stein, MD
Organizational Affiliation
GA - Piedmont Atlanta Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ram Subramanian, MD
Organizational Affiliation
GA - Emory University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nikolaos T Pyrsopoulos, MD
Organizational Affiliation
NJ - Rutgers University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Marquis Hart, MD
Organizational Affiliation
WA - Swedish Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Rohit Satoskar, MD
Organizational Affiliation
DC - Georgetown University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Talal Adhami, MD
Organizational Affiliation
OH - Cleveland Clinic Foundation
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Linda S Sher, MD
Organizational Affiliation
CA - Keck Hospital of USC
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Xaralambos Zervos, DO
Organizational Affiliation
FL - Cleveland Clinic Florida
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kalyan R Bhamidimarri, MD
Organizational Affiliation
FL - University of Miami Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Keck Hospital of USC
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
University of Miami Hospital
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Tampa General Hospital
City
Tampa
State/Province
Florida
ZIP/Postal Code
33606
Country
United States
Facility Name
Cleveland Clinic Floriday
City
Weston
State/Province
Florida
ZIP/Postal Code
33331
Country
United States
Facility Name
Piedmont Atlanta Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30309
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Minnesota Medical Center - Twin Cities Campus
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Rutgers University Hospital
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07102
Country
United States
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
New York University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Drexel University College of Medicine
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19102
Country
United States
Facility Name
Methodist Dallas Medical Center - The Liver Institute
City
Dallas
State/Province
Texas
ZIP/Postal Code
75203
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Swedish Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.vitaltherapies.com
Description
Vital Therapies, Inc. website

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Safety and Efficacy of the ELAD System (ELAD) to Treat Acute Liver Failure (ALF)

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