Severe Acute Alcoholic Hepatitis
Conditions
Keywords
liver failure, acute alcoholic hepatitis, patients failing steroid therapy, alcoholic hepatitis, steroid failure, Lille criteria, ELAD
Brief summary
The purpose of this study is to determine if treatment with the ELAD System is safe and effective in subjects with severe acute alcoholic hepatitis and Lille score failures (Lille score \>0.45).
Detailed description
The Lille score will be used to identify subjects with an increased risk of mortality (Lille score failures). The Lille score is a prognostic model combining six reproducible variables at Day 0 and Day 7 of steroid treatment. The Lille score used in this protocol is being used independent of steroid administration during the 7 days of evaluation. A Lille score \>0.45 (Lille score failure) indicates that the subject is at substantially increased risk of 30- and 90-day mortality. Subjects with severe acute alcoholic hepatitis (sAAH) are often treated with steroids as soon as their diagnosis is confirmed. This study is to assess treatment with the ELAD System in subjects who have failed per the Lille criteria, independent of steroid administration. ELAD treatment is done continuously for up to 10 days in addition to standard of care treatment. The Control group (those randomized not to receive ELAD treatment) will also get standard of care treatment. Standard of care is defined as the usual care for diet, medications, treatment of complications that may arise, etc. for sAAH patients.
Interventions
BIOLOGICALELAD
ELAD is an extracorporeal system that draws blood from the subject via a dual-lumen catheter placed in a large vein, and then separates the plasma fluid (ultrafiltrate) from cellular components using a specifically-designed ultrafiltrate generator cartridge. While the cellular components are returned to the subject via the venous access, the ultrafiltrate is circulated at a high flow rate through the four metabolically-active ELAD cartridges which contain cloned, immortalized human hepatoblastoma cells (VTL C3A cells) derived from a subclone of the human hepatoblastoma cell line HepG2.
OTHERStandard of Care treatment
Standard of care treatment is predefined treatment for sAAH complications (ascites, hepatic encephalopathy, varices, etc.) per AASLD/EASL Guidelines.
Sponsors
Vital Therapies, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 ; * Total bilirubin ≥8 mg/dL; * Medical history of alcohol abuse with evidence of a causal and temporal (\<6 weeks) relationship to the use of alcohol and hospital admission for this episode of sAAH; * Maddrey score ≥32 * A clinical diagnosis of severe acute alcoholic hepatitis (sAAH); * Subject must have liver biopsy or in investigator's opinion, if risk is too great to perform liver biopsy, then clinical diagnosis is sufficient; * Subject must be a Lille score failure (Lille score \>0.45) as defined in this study.
Exclusion criteria
* Platelet count \<50,000/mm3; * International Normalization Ratio (INR) \>3.0; * MELD score \>35; * Evidence of infection unresponsive to antibiotics; * Evidence of jaundice for \>3 months; * Hospital admission for any episodes of liver decompensation not related to sAAH, (other than this episode of sAAH) within the past 2 months; * Evidence of hemodynamic instability; * Evidence of active bleeding or of major hemorrhage defined as requiring ≥2 units of packed red blood cells to maintain a stable hemoglobin occurring within 48 hours of Screening; * Evidence of occlusive portal vein thrombosis impairing hepatopetal flow, or evidence of bile duct obstruction; * Evidence by physical exam, history, or laboratory evaluation of significant concomitant disease with expected life expectancy of less than 3 months; * Clinical evidence of liver size reduction due to cirrhosis, unless Investigator interpretation of the clinical evidence indicates liver size of \<10 cm or volume of \<750 cc is not considered reduced for the individual subject; * Chronic end-stage renal disease requiring chronic hemodialysis for more than 8 weeks (not classified as hepatorenal syndrome); * Uncontrolled seizures; * Positive serologies for viral hepatitis B or C; * Pregnancy as determined by β-human chorionic gonadotropin (HCG) results; * 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-210 clinical trial); * Currently listed or scheduled for liver transplant during the 90-day study period; * Previous liver transplant; * Previous participation in a clinical trial involving ELAD; * 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); * Refusal to participate in the VTI-210E follow-up study; * Is unable to provide an address for follow-up home visits. And other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to at least Study Day 91, with protocol VTI-208E providing additional survival data at the time of database lock (11 July 2016), approximately 27 months | The primary endpoint of the study was a comparison of overall survival (OS) between ELAD-treated and Control groups, with protocol VTI-210E providing additional survival data up to a maximum of 5 years, that was included as available at the time of database lock (11 July 2016). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Survivors at Study Day 91. | Up to Study Day 91. | Assess the proportion of survivors at Study Day 91. |
Countries
Germany, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ELAD (Plus Standard of Care) Participants randomized to the ELAD group received ELAD treatment plus protocol-directed Standard of Care treatment for a period of up to 10 days, followed by Standard of Care treatment through Study Day 91. | 9 |
| Standard of Care (Control) Participants randomized to the Control group received protocol-directed Standard of Care treatment in accord with AASLD and EASL guidelines for up to 91 days. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| VTI-210 | Death | 5 | 3 |
| VTI-210 | Withdrawal by Subject | 1 | 0 |
| VTI-210E | Death | 2 | 1 |
| VTI-210E | Study terminated prematurely | 1 | 5 |
Baseline characteristics
| Characteristic | Total | Standard of Care (Control) | ELAD (Plus Standard of Care) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 9 Participants | 9 Participants |
| Age, Continuous | 48.1 years STANDARD_DEVIATION 8.61 | 50.0 years STANDARD_DEVIATION 9.79 | 46.1 years STANDARD_DEVIATION 7.29 |
| Baseline MELD Score | 26.962 MELD Score STANDARD_DEVIATION 2.8484 | 26.323 MELD Score STANDARD_DEVIATION 2.8524 | 27.531 MELD Score STANDARD_DEVIATION 2.887 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 9 Participants | 9 Participants |
| Region of Enrollment Spain | 9 Participants | 6 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 4 Participants | 2 Participants | 2 Participants |
| Region of Enrollment United States | 5 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Female | 9 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 7 / 9 | 4 / 9 |
| other Total, other adverse events | 9 / 9 | 9 / 9 |
| serious Total, serious adverse events | 6 / 9 | 5 / 9 |
Outcome results
Primary
Overall Survival
The primary endpoint of the study was a comparison of overall survival (OS) between ELAD-treated and Control groups, with protocol VTI-210E providing additional survival data up to a maximum of 5 years, that was included as available at the time of database lock (11 July 2016).
Time frame: Up to at least Study Day 91, with protocol VTI-208E providing additional survival data at the time of database lock (11 July 2016), approximately 27 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ELAD (Plus Standard of Care) | Overall Survival | 2 Participants |
| Standard of Care (Control) | Overall Survival | 5 Participants |
Comparison: The primary endpoint was assessed using a Kaplan-Meier survival analysis of the Intent-to-Treat (ITT) population utilizing a log-rank test.p-value: 0.07695% CI: [0.085, 1.133]Log Rank
Secondary
Proportion of Survivors at Study Day 91.
Assess the proportion of survivors at Study Day 91.
Time frame: Up to Study Day 91.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ELAD (Plus Standard of Care) | Proportion of Survivors at Study Day 91. | 5 Participants |
| Standard of Care (Control) | Proportion of Survivors at Study Day 91. | 6 Participants |
p-value: 1Fisher Exact