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

• Sponsor: Vital Therapies, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01875874
• Collaborator: (none)
• Enrollment: 8
• Locations: 18
• Arm: 1
• Duration (Months): 47
• Patients Per Site: 0.4
• Patients Per Site Per Month: 0

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Liver Failure; Fulminant Hepatic Failure; Primary Graft Non-Function; Surgically-Induced Liver Failure	Biological: ELAD	Phase 2

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:

1. Fulminant Hepatic Failure (FHF) (acute liver failure with no preexisting liver disease);

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.

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Historically-Controlled Study to Assess Safety and Efficacy of ELAD in Subjects With Acute Liver Failure (ALF)
• Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Sep 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ELAD plus standard of care 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.	Biological: ELAD; 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).; Other Names: Human Cell-Based Bio-Artificial Liver Support System

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) of ALF Subjects [Study Day 1 through Study Day 28]

Secondary Outcome Measures

1. Number of Subjects Who Survived at the End of Study Day 28 or Who Received Orthotopic Liver Transplantation on or Before That Study Day. [Study Day 1 through Study Day 28]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Weight ≥ 40 kg;

2. Age ≥ 18;

3. Diagnosis of ALF attributed to one of the following:

4. FHF (acute liver failure with no preexisting liver disease, see below);

5. Primary Graft Non-Function (PNF);

6. 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);

7. 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;

8. 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:

1. Known acetaminophen ingestion or diagnostic serum level, and at least one of the following:

2. Prothrombin time (PT) > 100 seconds [International Normalized Ratio (INR) > 6.5], OR

3. Encephalopathy Grade 3 or 4 AND ARTERIAL AMMONIA >100 umol/liter and at least one of the following:

1. 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;

1. Creatinine > 2.5 mg/dL; OR

1. 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:

5. Presence of sepsis or septic shock; OR

6. Positive blood cultures (bacteremia, fungemia) within 72 hours prior to Enrollment; OR

7. Presence of spontaneous bacterial peritonitis during the 2 days prior to Enrollment; OR

8. Clinical and radiological signs of pneumonia.

9. 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);

10. Portal hypertension;

11. Liver dysfunction due to trauma;

12. Irreversible brain death;

13. 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]

14. Cardiovascular sepsis-related organ failure assessment score (SOFA score) >3;

15. Stroke or intracranial hemorrhage;

16. Seizures uncontrolled by medication;

17. Acute myocardial infarction;

18. 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;

19. Acute Respiratory Distress Syndrome;

20. Pregnancy as determined by beta-human chorionic gonadotropin (β-hCG) results;

21. ≤ 2 weeks postpartum;

22. 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);

23. Prior ELAD therapy;

24. 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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Keck Hospital of USC	Los Angeles	California	United States	90033
2	Georgetown University Hospital	Washington	District of Columbia	United States	20007
3	University of Miami Hospital	Miami	Florida	United States	33136
4	Tampa General Hospital	Tampa	Florida	United States	33606
5	Cleveland Clinic Floriday	Weston	Florida	United States	33331
6	Piedmont Atlanta Hospital	Atlanta	Georgia	United States	30309
7	Emory University Hospital	Atlanta	Georgia	United States	30322
8	Rush University Medical Center	Chicago	Illinois	United States	60612
9	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
10	University of Minnesota Medical Center - Twin Cities Campus	Minneapolis	Minnesota	United States	55455
11	Rutgers University Hospital	Newark	New Jersey	United States	07102
12	Montefiore Medical Center	Bronx	New York	United States	10467
13	New York University Medical Center	New York	New York	United States	10016
14	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
15	Drexel University College of Medicine	Philadelphia	Pennsylvania	United States	19102
16	Methodist Dallas Medical Center - The Liver Institute	Dallas	Texas	United States	75203
17	University of Utah	Salt Lake City	Utah	United States	84132
18	Swedish Medical Center	Seattle	Washington	United States	98104

Sponsors and Collaborators

• Vital Therapies, Inc.

Investigators

• Study Chair: Jan Stange, MD, Ph.D., Vital Therapies, Inc.
• Principal Investigator: Parvez Mantry, MD, TX - Methodist Dallas Medical Center - The Liver Institute
• Principal Investigator: David J Reich, MD, PA - Drexel University College of Medicine
• Principal Investigator: Paul J Gaglio, MD, NY - Montefiore Medical Center
• Principal Investigator: Juan Gallegos-Orozco, MD, UT - University of Utah
• Principal Investigator: Angel Alsina, MD, FL - Tampa General Hospital
• Principal Investigator: Lewis W Teperman, MD, NY - New York University Medical Center
• Principal Investigator: Nikunj Shah, MD, IL - Rush University Medical Center
• Principal Investigator: Julie Thompson, MD, MN - University of Minnesota Medical Center - Twin Cities Campus
• Principal Investigator: Winfred W Williams, Jr., MD, MA - Massachusetts General Hospital
• Principal Investigator: Lance Stein, MD, GA - Piedmont Atlanta Hospital
• Principal Investigator: Ram Subramanian, MD, GA - Emory University Hospital
• Principal Investigator: Nikolaos T Pyrsopoulos, MD, NJ - Rutgers University Hospital
• Principal Investigator: Marquis Hart, MD, WA - Swedish Medical Center
• Principal Investigator: Rohit Satoskar, MD, DC - Georgetown University Hospital
• Principal Investigator: Talal Adhami, MD, OH - Cleveland Clinic Foundation
• Principal Investigator: Linda S Sher, MD, CA - Keck Hospital of USC
• Principal Investigator: Xaralambos Zervos, DO, FL - Cleveland Clinic Florida
• Principal Investigator: Kalyan R Bhamidimarri, MD, FL - University of Miami Hospital

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Vital Therapies, Inc. website

Publications

None provided.

• Responsible Party: Vital Therapies, Inc.
• ClinicalTrials.gov Identifier: NCT01875874
• Other Study ID Numbers: VTI-212
• First Posted: Jun 12, 2013
• Last Update Posted: Feb 12, 2019
• Last Verified: Jan 1, 2019

• Keywords provided by Vital Therapies, Inc.: liver failure; acute liver failure; fulminant hepatic failure; primary graft non-function; surgically-induced liver failure; ELAD; ALF; FHF; PNF
• Additional relevant MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Failure, Acute

Study Results

Participant Flow

Arm/Group Title	ELAD System (ELAD) Treatment Plus Standard of Care Treatment
Arm/Group Description	Continuous treatment with the ELAD System (ELAD) 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. ELAD: 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).
Period Title: Overall Study
STARTED	8
COMPLETED	5
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	ELAD Treatment Plus Standard of Care Treatment
Arm/Group 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. ELAD: 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).
Overall Participants	8
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 87.5%
>=65 years	1 12.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	38.5 (19.99)
Sex: Female, Male (Count of Participants)
Female	6 75%
Male	2 25%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 12.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 25%
White	5 62.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	8 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) of ALF Subjects
Time Frame	Study Day 1 through Study Day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ELAD Treatment Plus Standard of Care Treatment
Arm/Group 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. ELAD: 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).
Measure Participants	8
Count of Participants [Participants]	5 62.5%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	ELAD System (ELAD) Treatment Plus Standard of Care Treatment
Arm/Group Description	Continuous treatment with the ELAD System (ELAD) 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. ELAD: 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).
Measure Participants	8
Count of Participants [Participants]	5 62.5%

Adverse Events

Adverse Event Reporting Description	One subject was not treated with ELAD due to substantial improvement of their condition prior to treatment initiation. Therefore, only 7 subjects were exposed to ELAD treatment and at risk for adverse events.
Arm/Group Title	ELAD Treatment Plus Standard of Care Treatment
Arm/Group 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. ELAD: 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).
All Cause Mortality
	ELAD Treatment Plus Standard of Care Treatment
	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)
Serious Adverse Events
	ELAD Treatment Plus Standard of Care Treatment
	Affected / at Risk (%)	# Events
Total	6/7 (85.7%)
Blood and lymphatic system disorders
Anaemia	2/7 (28.6%)	2
Thrombocytopenia	1/7 (14.3%)	1
Gastrointestinal disorders
Upper gastrointestinal haemorrhage	1/7 (14.3%)	1
General disorders
Multi-organ failure	3/7 (42.9%)	3
Hepatobiliary disorders
Autoimmune hepatitis	1/7 (14.3%)	1
Immune system disorders
Liver transplant rejection	1/7 (14.3%)	2
Metabolism and nutrition disorders
Hyperammonaemia	1/7 (14.3%)	1
Hyperglycaemia	1/7 (14.3%)	1
Nervous system disorders
Cerebral haemorrhage	1/7 (14.3%)	1
Hepatic encephalopathy	1/7 (14.3%)	1
Vascular disorders
Hypertension	1/7 (14.3%)	1
Other (Not Including Serious) Adverse Events
	ELAD Treatment Plus Standard of Care Treatment
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Blood and lymphatic system disorders
Anaemia	5/7 (71.4%)	6
Anaemia macrocytic	1/7 (14.3%)	1
Hypofibrinogenaemia	2/7 (28.6%)	2
Leukocytosis	3/7 (42.9%)	3
Leukopenia	1/7 (14.3%)	1
Cardiac disorders
Arrhythmia supraventricular	1/7 (14.3%)	1
Cyanosis	1/7 (14.3%)	1
Pericardial effusion	1/7 (14.3%)	1
Sinus bradycardia	1/7 (14.3%)	1
Sinus tachycardia	1/7 (14.3%)	1
Tachycardia	4/7 (57.1%)	4
Ventricular arrhythmia	1/7 (14.3%)	1
Eye disorders
Dry eye	1/7 (14.3%)	1
Gastrointestinal disorders
Abdominal distension	1/7 (14.3%)	1
Abdominal pain	1/7 (14.3%)	1
Abdominal pain upper	1/7 (14.3%)	1
Ascites	1/7 (14.3%)	1
Constipation	2/7 (28.6%)	2
Diarrhoea	2/7 (28.6%)	2
Dysphagia	1/7 (14.3%)	1
Ileus	1/7 (14.3%)	1
Melaena	1/7 (14.3%)	1
Nausea	2/7 (28.6%)	2
Oral mucosa erosion	1/7 (14.3%)	1
Pancreatitis	1/7 (14.3%)	1
Vomiting	1/7 (14.3%)	1
General disorders
Application site necrosis	1/7 (14.3%)	1
Catheter site haematoma	1/7 (14.3%)	1
Catheter site haemorrhage	3/7 (42.9%)	3
Chest pain	1/7 (14.3%)	1
Chills	1/7 (14.3%)	1
Gait disturbance	1/7 (14.3%)	1
Generalized oedema	1/7 (14.3%)	1
Hypothermia	1/7 (14.3%)	1
Oedema peripheral	2/7 (28.6%)	2
Pain	1/7 (14.3%)	1
Peripheral swelling	1/7 (14.3%)	1
Pyrexia	4/7 (57.1%)	5
Hepatobiliary disorders
Bile duct stenosis	1/7 (14.3%)	1
Biliary fistula	1/7 (14.3%)	1
Cholangitis	1/7 (14.3%)	1
Infections and infestations
Clostridium difficile colitis	1/7 (14.3%)	1
Pneumonia	2/7 (28.6%)	3
Sepsis	1/7 (14.3%)	1
Urinary tract infection	1/7 (14.3%)	1
Injury, poisoning and procedural complications
Complications of transplant surgery	2/7 (28.6%)	2
Hepatic haematoma	1/7 (14.3%)	1
Laceration	1/7 (14.3%)	1
Wound	1/7 (14.3%)	1
Investigations
Alpha 1 foetoprotein increased	1/7 (14.3%)	1
Amylase increased	1/7 (14.3%)	1
Body temperature increased	1/7 (14.3%)	1
Candida test positive	1/7 (14.3%)	1
Electrocardiogram QT prolonged	1/7 (14.3%)	1
Electrocardiogram ST segment elevation	1/7 (14.3%)	1
Electrocardiogram T wave inversion	1/7 (14.3%)	1
Liver function test abnormal	1/7 (14.3%)	1
Occult blood positive	2/7 (28.6%)	2
Oxygen saturation decreased	1/7 (14.3%)	1
Metabolism and nutrition disorders
Fluid overload	1/7 (14.3%)	1
Hyperammonaemia	1/7 (14.3%)	1
Hyperglycaemia	2/7 (28.6%)	2
Hypermagnesaemia	2/7 (28.6%)	2
Hyperphosphataemia	2/7 (28.6%)	2
Hypervolaemia	1/7 (14.3%)	1
Hypocalcaemia	1/7 (14.3%)	1
Hypochloraemia	1/7 (14.3%)	1
Hypokalaemia	2/7 (28.6%)	2
Hyponatraemia	1/7 (14.3%)	1
Hypophosphataemia	1/7 (14.3%)	1
Hypovolaemia	2/7 (28.6%)	2
Musculoskeletal and connective tissue disorders
Muscular weakness	1/7 (14.3%)	1
Pain in extremity	1/7 (14.3%)	1
Nervous system disorders
Brain injury	1/7 (14.3%)	1
Intracranial pressure increased	1/7 (14.3%)	1
Psychiatric disorders
Agitation	2/7 (28.6%)	2
Anxiety	1/7 (14.3%)	1
Delirium	1/7 (14.3%)	1
Insomnia	3/7 (42.9%)	3
Respiratory, thoracic and mediastinal disorders
Atelectasis	1/7 (14.3%)	1
Cough	1/7 (14.3%)	1
Epistaxis	1/7 (14.3%)	1
Haemoptysis	2/7 (28.6%)	2
Hypoxia	1/7 (14.3%)	1
Pharyngeal haemorrhage	1/7 (14.3%)	1
Pleural effusion	4/7 (57.1%)	4
Pneumonia aspiration	1/7 (14.3%)	1
Pulmonary embolism	1/7 (14.3%)	1
Respiratory acidosis	1/7 (14.3%)	1
Skin and subcutaneous tissue disorders
Ecchymosis	1/7 (14.3%)	1
Pruritus	1/7 (14.3%)	1
Rash maculo-papular	1/7 (14.3%)	1
Vascular disorders
Deep vein thrombosis	1/7 (14.3%)	1
Hypertension	2/7 (28.6%)	2
Hypotension	4/7 (57.1%)	5

Limitations/Caveats

This study was terminated early, after enrollment of only 8 out of 40 planned subjects, due to findings from previous VTI-208 study. Thus, sample size of VTI-212 was very small leading to statistical analyses that cannot be meaningfully interpreted.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.