Liver Transplantation in Alcoholic Hepatitis (SETH-HA)

Applicability of Liver Transplantation in Alcoholic Hepatitis

Patients with alcoholic hepatitis non-responsive to steroids have a poor prognosis. Recently a French-Belgian prospective study has obtained good results (acceptable survival with a low rate of alcohol recidivism).

The hypothesis of the present study is that carefully selected Spanish patients with alcoholic hepatitis that do not respond to steroid therapy may have a good survival if they receive a liver transplant. The expected rate of alcohol recidivism in such a selected population will be low.

Study Overview

• Status: Suspended
• Conditions: Alcoholic Hepatitis

Detailed Description

This is a open prospective multicenter study. Nineteen liver transplant units in Spain will take part in it.

Inclusion criteria for patients:

1. Diagnosis of alcoholic hepatitis (liver biopsy will be advisable).
2. First episode of clinical decompensation of alcoholic liver disease (defined as jaundice, variceal bleeding, ascites or portal-systemic encephalopathy).
3. Absence of a high risk of alcoholic recidivism (according to De Gottardi, et al).
4. Severe alcoholic hepatitis (ABIC score > 6.71)
5. Informed consent

Exclusion criteria :

1. Age over 65 years.
2. Hepatitis B or C or HIV infections.
3. Uncontrolled bacterial infection
4. Other liver diseases, such as alpha-1-antitrypsin deficiency, primary biliary cirrhosis, ...
5. Morbid obesity (BMI > 35 kg/m2)
6. Major uncontrolled psychiatric disease
7. Drug addiction (excluding tobacco) in the last two years.
8. Absence of informed consent.
9. Acute-on-chronic liver disease.
10. Paracetamol consumption over 10 grams in the last week.

Criteria for liver transplantation.

1. Absence of response to steroid therapy (Lille score ≥ 0.45 7 days after initiation of steroid therapy).
2. Adequate social and familiar environment.
3. Complete agreement in the medical staff about the candidate to transplantation.
4. Absence of bacterial or fungal infection.

Three groups of patients will be formed:

Group 1. Patients with severe alcoholic hepatitis and good response to therapy. Group 2. Patients with severe alcoholic hepatitis and poor response to therapy, that are not candidates to transplantation.

Group 3. Patients with severe alcoholic hepatitis and poor response to therapy, that are candidates to transplantation.

A complete follow-up of the patients would be extended to five years. The survival of these three groups will be compared. Survival of liver transplant recipients should also be compared with survival of other liver transplant recipients.

Alcohol recidivism should also be studied in all the patients of the study. Sample size estimation: According to the data published by Mathurin et al, 28 patients treated with liver transplantation and 28 non-transplanted patients with severe alcoholic hepatitis should be necessary.

Interim analysis after every 10 transplanted patients should be performed. The study will be interrupted if the differences in the survivals between groups 2 and 3 reaches a significance of 0.01. In case this significance is not reached the inclusion of patients should end when 40 patients are transplanted. This sample size is estimated to be reached in 18-24 months.

• Study Type: Observational
• Enrollment (Anticipated): 40

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain
    • Hospital Vall d'Hebron
  • Córdoba, Spain
    • Hospital Reina Sofia
  • Granada, Spain
    • Hospital Virgen de la Nieves
  • La Coruña, Spain
    • Complejo Hospitalario Universitario de La Coruña
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Madrid, Spain
    • Hospital Gregorio Marañón
  • Murcia, Spain
    • Hospital Virgen de la Arrixaca
  • Málaga, Spain
    • Hospital Carlos Haya
  • Sevilla, Spain
    • Hospital Virgen Del Rocio
  • Valencia, Spain
    • Hospital La Fe
  • Valladolid, Spain
    • Hospital Rio Hortega
  • Zaragoza, Spain
    • Hospital Lozano Blesa
  • Asturias
    • Oviedo, Asturias, Spain
      • Hospital Central de Asturias
  • Cantabria
    • Santander, Cantabria, Spain
      • Hospital Marques de Valdecilla
  • La Coruña
    • Santiago de Compostela, La Coruña, Spain
      • Hospital Clinico Universitario de Santiago
  • Madrid
    • Majadahonda, Madrid, Spain
      • Hospital Puerta de Hierro
  • Navarra
    • Pamplona, Navarra, Spain
      • Clinica Universidad de Navarra

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with alcoholic hepatitis participating in this trial are going to be selected from patients admitted to the hospital (from the emergency department or referred from other hospital)

Description

Inclusion Criteria:

1. Diagnosis of alcoholic hepatitis (liver biopsy will be advisable).
2. First episode of clinical decompensation of alcoholic liver disease (defined as jaundice, variceal bleeding, ascites or portal-systemic encephalopathy).
3. Absence of a high risk of alcoholic recidivism (according to De Gottardi, et al).
4. Severe alcoholic hepatitis (ABIC score > 6.71)
5. Informed consent

Exclusion Criteria:

1. Age over 65 years.
2. Hepatitis B or C or HIV infections.
3. Uncontrolled bacterial infection
4. Other liver diseases, such as alpha-1-antitrypsin deficiency, primary biliary cirrhosis, ...
5. Morbid obesity (BMI > 35 kg/m2)
6. Major uncontrolled psychiatric disease
7. Drug addiction (excluding tobacco) in the last two years.
8. Absence of informed consent.
9. Acute-on-chronic liver disease.
10. Paracetamol consumption over 10 grams in the last week.

Criteria for liver transplantation.

1. Absence of response to steroid therapy (Lille score ≥ 0.45 7 days after initiation of steroid therapy).
2. Adequate social and familiar environment.
3. Complete agreement in the medical staff about the candidate to transplantation.
4. Absence of bacterial or fungal infection.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Good response; Patients with severe alcoholic hepatitis and good response to therapy.
Non transplant candidates; Patients with severe alcoholic hepatitis and poor response to therapy, that are not candidates to transplantation, according to the specified criteria.
Transplant candidates; Patients with severe alcoholic hepatitis and poor response to therapy, that are candidates to transplantation, according to the specified criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate survival of patients with severe alcoholic hepatitis non responsive to therapy after liver transplantation	The survival of patients transplanted with alcoholic hepatitis is going to be compared with the survival of patients with alcoholic hepatitis that are not considered adequate for liver transplantation	1 year after the diagnosis of alcoholic hepatitis

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the applicability of liver transplantation in patients with alcoholic hepatitis non responsive to steroid therapy	The applicability of liver transplantation is defined as the ratio between the number of patients transplanted for alcoholic hepatitis and the number of patients with severe alcoholic hepatitis that do not respond to steroid therapy.	1 year
Evaluate the mortality in waiting list for transplantation of patients with alcoholic hepatitis unresponsive to steroid therapy	Proportion of patients who are accepted as candidates for liver transplantation who die before transplantation.	1 year
Evaluate the rate of alcohol recidivism after liver transplantation for alcoholic hepatitis	Proportion of patients transplanted for alcoholic hepatitis that have a recurrence in alcohol consumption	1, 2, 3, 4 and 5 years
Evaluate survival of patients with alcoholic hepatitis after liver transplantation.	The survival of patients transplanted with alcoholic hepatitis is going to be compared with the survival of patients with alcoholic hepatitis that are not considered adequate for liver transplantation	2, 3, 4 and 5 years after the diagnosis of alcoholic hepatitis

Collaborators and Investigators

• Sponsor: Sociedad Española de Trasplante Hepático
• Collaborators: Fundación Mutua Madrileña
• Investigators: Study Chair: Ignacio Herrero, MD, Clinica Universidad de Navarra; Study Chair: Santiago Tome, MD, Complejo Hospitalario Universitario de Santiago; Study Chair: Ignacio Gonzalez-Pinto, MD, Hospital Central de Asturias

Publications and helpful links

General Publications

• Dominguez M, Rincon D, Abraldes JG, Miquel R, Colmenero J, Bellot P, Garcia-Pagan JC, Fernandez R, Moreno M, Banares R, Arroyo V, Caballeria J, Gines P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008 Nov;103(11):2747-56. doi: 10.1111/j.1572-0241.2008.02104.x. Epub 2008 Aug 21.
• Tome S, Martinez-Rey C, Gonzalez-Quintela A, Gude F, Brage A, Otero E, Abdulkader I, Forteza J, Bustamante M, Varo E. Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J Hepatol. 2002 Jun;36(6):793-8. doi: 10.1016/s0168-8278(02)00047-8.
• Wells JT, Said A, Agni R, Tome S, Hughes S, Dureja P, Lucey MR. The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation. Liver Transpl. 2007 Dec;13(12):1728-35. doi: 10.1002/lt.21298.
• Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, Castel H, Duhamel A, Pageaux GP, Leroy V, Dharancy S, Louvet A, Boleslawski E, Lucidi V, Gustot T, Francoz C, Letoublon C, Castaing D, Belghiti J, Donckier V, Pruvot FR, Duclos-Vallee JC. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med. 2011 Nov 10;365(19):1790-800. doi: 10.1056/NEJMoa1105703.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Anticipated): December 1, 2014
• Study Completion (Anticipated): December 1, 2017

Study Registration Dates

• First Submitted: December 29, 2012
• First Submitted That Met QC Criteria: January 13, 2013
• First Posted (Estimate): January 15, 2013

Study Record Updates

• Last Update Posted (Estimate): June 3, 2014
• Last Update Submitted That Met QC Criteria: June 2, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Liver transplantation; Survival; Alcoholism; Alcoholic hepatitis
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Liver Diseases; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Liver Diseases, Alcoholic; Alcohol-Induced Disorders; Hepatitis; Hepatitis A; Hepatitis, Alcoholic
• Other Study ID Numbers: SETH-HA