Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial

Abstract

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

Trial registration: ClinicalTrials.gov NCT01471028.

© 2017 The Authors. Liver Transplantation published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

Figures

Figure 1

The ELAD system is an extracorporeal human hepatic cell‐based liver treatment. During ELAD treatment, blood is drawn from the subject via a dual‐lumen catheter using an extracorporeal pumping unit, and then is separated by a specifically designed UF generator cartridge. The UF contains proteins the size of albumin and smaller but does not contain larger proteins such as antibodies. The UF is circulated at a high flow rate through the ELAD cartridges, which contain approximately 440 g of C3A cells. After circulation through the ELAD cartridges, the UF passes through a 0.2‐µm pore size cell filter, is recombined with the cellular components of the subject's blood, and is then returned to the subject via the dual‐lumen catheter.

Figure 2

Flowchart and disposition of patients during the study until July 2015. Of the 374 subjects screened for the study, 171 did not meet inclusion criteria or presented with exclusion criteria, most frequently the inability to provide informed consent (n = 39), MELD score > 35 (n = 44), evidence of reduction in total bilirubin of 20% or more in the previous 72 hours (n = 42), and evidence of significant concomitant disease with expected life expectancy of

Figure 3

The Kaplan‐Meier analysis is given for the ITT population. At database lock, 46 subjects had died in the ELAD group and 53 in the control group. Remaining at risk were 49 in the ELAD group and 53 in the control group.

Figure 4

The Kaplan‐Meier analysis is given for the prespecified subgroup analysis with respect to age and baseline MELD. (upper right) The subgroup with age  47 years, at database lock, 32 subjects had died in the ELAD group and 25 in the control group. Remaining at risk were 20 in the ELAD group and 22 in the control group. (lower right) The subgroup with MELD  28, at database lock, 31 subjects had died in the ELAD group and 21 in the control group. Remaining at risk were 14 in the ELAD group and 16 in the control group.

Figure 5

The IL1Ra concentrations of a subset of ELAD (n = 14) and control patients (n = 11) is depicted as means and standard errors. The IL1Ra analysis was conducted on a subset of VTI‐ 208 subjects that met the inclusion criteria for the follow‐up study, VTL 308 (NCT02612428), which focuses on a population with lower MELD and age. Subjects were only included in this subset if they had a full sample set, which included samples from Baseline, Study Days 3, 5, and 7, as well as at least 1 sample from a follow‐up at either 14 or 28 days. Although levels were comparable at baseline, the difference between levels in ELAD versus control subjects was significant (P < 0.05, MWU‐test) at study days 3, 5, and 7 (1 week). Also, in the Wilcoxon signed rank test, IL1Ra levels were elevated compared with baseline significantly at study day 3, 5, and 7 in ELAD patients (P < 0.05), but not in controls.