Novel Therapies in Severe Alcoholic Hepatitis

Study ID
STU 082012-007

Cancer Related
No

Healthy Volunteers
No

Study Sites

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

Principal Investigator
Mack Mitchell

Summary

our study 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. Steroid monotherapy is not effective in all patients with aaH. Consequently, our studies will utilize compounds that have the potential to improve gut barrier function (both in moderate and severe disease) anD to reduce the associated inflammation (severe disease) anD to prevent the development of hepatorenal syndrome and other organ failure (severe disease).

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 MeLD [GreaterThanorequalTo] 20. Those stratified into the moderate 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 but require that patients in the severe group also have a DF [Greater Than] 32, to avoid including patients with chronic kidney disease, not hepatorenal syndrome.

Specific aim 1 [?] Randomized controlled trial for severe acute alcoholic hepatitis: MeLD [GreaterThanorequalTo] 20:
Patients with severe aaH will be randomized equally into two arms. Patients with MeLD 20-25, patients with MeLD 26-31, and patients with MeLD [Greater Than] 31 will be randomized separately into two equal arms to ensure comparable severity in the three groups. The trial will also be double-blinded by re-packaging all oral medications into capsules to ensure that each group receives an equal number of capsules each day for the entire duration of the study. Patients will be treated with pentoxifylline 400 mg three times daily for 28 days PLuS zinc supplements for a total of 6 months (Group a) or prednisolone 32 mg daily for 28 days PLuS placebo capsules daily for the remaining 5 months (Group B). an injection of either anakinra (100 mg), Group a) or a placebo (Group B) will be given subcutaneously each day for 14 days. Patients, investigators and physicians involved in the care of the patients will be blinded as to the treatment.

The primary outcome will be 6-month mortality. Secondary outcomes will include 30 and 90 day mortality; changes in MeLD score at 30, 90 and 180 days and changes in gut mucosal permeability measured by the lactulose/mannitol test.

Specific aim 2 [?] natural history of severe acute alcoholic hepatitis: MeLD [GreaterThanorequalTo] 20:
Patients with 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, leukocytes, hepatomegaly, AND
e. Elevation of AST > 80 U/L, but < 500 U/L at the time of admission or within 3 days 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 and Maddrey >= 32
h. Willingness to utilize two reliable forms of contraception (both males and females of
childbearing potential) from screening through the first six weeks of the study