Novel Therapies in Moderately Severe Alcoholic Hepatitis

Study ID
STU 092012-012

Cancer Related
No

Healthy Volunteers
No

Study Sites

Contact
Rosa Dehoyos
469/463-2998
rosa.dehoyos@utsouthwestern.edu

Principal Investigator
Mack Mitchell

Summary

our studies will test the hypothesis that the syndrome of acute alcoholic hepatitis (aaH) results from severe inflammation and dysregulated cytokines, providing the [Quote]second hit[Quote] that causes an acute deterioration. We further hypothesize that gut derived endotoxins and other bacterial products trigger inflammation and are a consequence of increased permeability with altered gut barrier function.

We will utilize published models for predicting mortality in patients with aaH to stratify patients based on severity. although previous studies of treatment for severe aaH utilized 30-day mortality as an endpoint, 6-month mortality is a more relevant outcome, in part because most transplantation programs require 6 months of abstinence before active listing. Furthermore, the number of deaths between 6 and12 months in abstinent patients is low compared to the number in the first 6 months. Patients will be stratified into those with Model of end-stage Liver Disease (MeLD) score [Less Than] 20 and MeLDMeLD [GreaterThanorequalTo]20. Those stratified into the severe group are described in a separate application. The primary difference between the Maddrey discriminant function (DF) and the MeLD is that the latter includes creatinine. We propose to use the MeLD score to stratify for severity.

Specific aim 1 [?] Randomized controlled trial for moderate alcoholic hepatitis: MeLD [Less Than] 20:
Patients with moderate aaH will be randomized to receive either standard of care plus placebo or standard of care plus probiotic capsules in a 1:1 ratio.
The primary outcome will be 30-day change in MeLD score from baseline. Secondary outcomes will be change in MeLD score from baseline at 90 and 180 days and changes from baseline in the gut mucosal integrity as assessed by the lactulose/mannitol test. Changes in serum endotoxin levels and cytokine profiles including TnF [and] #945; will also be measured as secondary outcomes. We predict that probiotics will stabilize gut-barrier function, decrease endotoxemia, accelerate improvement in liver enzymes, and may slow or prevent progression of liver disease.

Specific aim 2 [?] natural history of moderately severe acute alcoholic hepatitis: MeLD [Less Than] 20:
Patients with moderately severe aaH who decline to be randomized but consent to prospective data collection and minimal risk non-invasive studies (blood drawing and urine collection)

Specific aim 3 [?] Subjects will be asked for a Dna blood draw during the first day of the study.

all human subjects will be patients with a clinical presentation consistent with acute alcoholic hepatitis (aaH). The trial is designed to test the hypothesis that aaH results from inflammation triggered by gut derived endotoxins and other bacterial products as a consequence of increased permeability of the gut mucosa. Patients with aaH will be stratified by disease severity as determined by the Model for end-Stage Liver Disease (MeLD) score and enrolled in one of two randomized controlled trials.

Participant Eligibility

a) Ability to provide informed consent by subject or appropriate family member
b) Age between 21-70 years
c) Recent alcohol consumption > 50 g/d for > 6 months, continuing within two months before enrollment
d) At least 2 of the following symptoms or signs of acute alcoholic hepatitis: Anorexia, nausea, RUQ pain, jaundice, leukocytosis, hepatomegaly AND
e) Elevation of AST > 80 U/L, but < 500 U/L at the time of admission or within 3 dyas of baseline visit; AST > ALT and ALT < 200 U/L; total bilirubin > 3 mg/dL AND
f) Liver biopsy showing alcoholic hepatitis (steatohepatitis) OR ultrasound of liver showing increased echogenicity OR CT scan showing decreased attenuation of liver compared to spleen OR MRI showing fatty liver (decreased signaling intensity on T1 weighted images). If the liver biopsy (done within 60 days of inclusion) confirms diagnosis of AAH then inclusion e will be waived.
g) Model for End-Stage Liver Disease (MELD) <20
h) Willingness to utilize two reliable forms of contraception (both males and females of childbearing potential) from screening through the first six weeks of study.