Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis (CorpentoxHAA)

Evaluation of the Survival Benefit of the Adjunction of Pentoxifylline to Corticosteroids in Patients Suffering From Severe Alcoholic Hepatitis

The treatment of severe forms of alcoholic hepatitis (AH) constitutes a major challenge for clinicians involved in the management of severe alcoholic liver disease. In patients with Maddrey function higher than 32, compelling evidence from data has shown that corticosteroids improve short-term survival. However, novel strategies or molecules are required in light of the fact that approximately 40 % of patients continue to die at 6 months. A double-blinded randomized controlled trial of 101 patients has showed that Pentoxifylline improves survival of patients with severe AH, as compared to placebo. In terms of mechanisms, the effect of pentoxifylline is related to prevention of hepatorenal function whereas corticosteroids induce an early improvement in liver function. When considering these differences of mechanisms, many clinicians suggest that the addition of pentoxyfilline to corticosteroids is an attractive option that needs to be tested in patients with severe AH.

Study Overview

• Status: Completed
• Conditions: Alcoholic Liver Disease; Alcoholic Hepatitis
• Intervention / Treatment: Drug: placebo; Drug: Pentoxifylline

Detailed Description

The aim of the present study is to determine whether or not the adjunction of Pentoxifylline to corticosteroids would improve 6-month survival of patients with severe alcoholic hepatitis. This multicenter, randomized, double-blinded, controlled, phase 3 trial was conducted in 24 centers located in France and Belgium. Alcoholic hepatitis was biopsy-proven. All eligible patients were randomly assigned in a 1:1 ratio to receive corticosteroids + Pentoxifylline or corticosteroids + Placebo. The primary outcome of the study was 6-month survival. Assuming a two-sided type I error of 0.05, a randomization ratio of 1:1 between the 2 groups, 6-month survival of 64% in the Placebo and Corticosteroids group and of 78 % in the Pentoxifylline and Corticosteroids group, we estimated that with 268 randomized patients (134 in each group), the study would have a power of 80% to detect this increase in 6-month survival in the Pentoxifylline and Corticosteroid group.

• Study Type: Interventional
• Enrollment (Actual): 278
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1070
    • University Hospital
• France
  • Angers, France, 49933
    • University Hospital
  • Bondy, France, 93143
    • Hôpital Jean Verdier (AH-HP)
  • Bordeaux, France, 33000
    • University Hospital
  • Béthune, France, 62408
    • Centre Hospitalier
  • Caen, France, 14000
    • University Hospital
  • Clamart, France, 92141
    • Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)
  • Clichy, France, 92118
    • Hôpital Beaujon (AH-HP)
  • Creil, France, 60100
    • Centre Hospitalier
  • Créteil, France, 94000
    • Hôpital Henri Mondor (AP-HP)
  • Dunkerque, France, 59240
    • Centre Hospitalier
  • Lens, France, 62300
    • Centre Hospitalier
  • Lille, France, 59037
    • University Hospital
  • Maubeuge, France, 59600
    • Centre hospitalier Sambre en avesnois
  • Montpellier, France, 34295
    • University Hospital
  • Nantes, France, 45000
    • University Hospital
  • Nice, France, 06202
    • University Hospital
  • Paris, France, 75012
    • Hôpital Saint Antoine (AP-HP)
  • Paris, France, 75013
    • Hôpital de la Pitié-Salpétrière (AP-HP)
  • Paris, France, 75014
    • Hôpital Cochin (AH-HP)
  • Poitiers, France, 49000
    • University Hospital
  • Rennes, France, 35033
    • University Hospital
  • Roubaix, France, 59100
    • Centre hospitalier Victor Provo
  • Strasbourg, France, 67100
    • University Hospital
  • Tourcoing, France, 59208
    • Centre Hospitalier
  • Valenciennes, France, 59300
    • Centre Hospitalier
  • Vandoeuvre les nancy, France, 54511
    • University Hospital, Nancy
  • Villejuif, France, 94000
    • Hôpital Paul Brousse (AH-HP)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Alcohol consumption more than 40 gram/day for women and 50 gram/day for men
• Maddrey discriminant function higher than 32
• Onset of jaundice within the 3 previous months
• Biopsy-proven alcoholic hepatitis

Exclusion Criteria:

• Hypersensitivity to pentoxifylline
• Any severe disease that may potential affect survival such as cardiac failure, ischemic cardiopathy, respiratory failure
• Any neoplasm that occurred within the 2 previous years
• Hepatocellular carcinoma or any previous diagnosis of hepatocellular carcinoma
• Portal thrombosis
• Severe gastrointestinal bleeding
• Uncontrolled sepsis within the 7 previous days
• Hepatorenal syndrome type I
• Viral and fungal infection
• Acute pancreatitis
• Any tuberculosis that occurred within the 5 previous years
• Psychiatric disorders that contraindicate the use of corticosteroids
• Infection related to virus of the hepatites B or C
• HIV infection (Human immunodeficiency virus)
• Any treatment with corticosteroids, immunosuppressive agents, budesonide, thalidomide or pentoxifylline that was given within the previous year
• Pregnancy or breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Pentoxifylline + Prednisolone; Pentoxifylline 400 mg prolonged-released tablets 3 time a day [1200 mg/day] + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]	Drug: placebo; prolonged-release tablets 3 time per day for 1 month
Placebo Comparator: Placebo + Prednisolone; Placebo prolonged-release tabled 3 time a day + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]	Drug: Pentoxifylline; 400 mg prolonged-released tablets 3 time per day for 1 month.; Other Names: TORENTAL 400MG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Hepatorenal syndrome	6 months
Score of Lille model	Seven days
Percentage of Meld score (Model for End-stage Liver Disease) higher than 17	6 months

Collaborators and Investigators

• Sponsor: University Hospital, Lille
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Philippe MATHURIN, MD PhD, University Hospital, Lille

Publications and helpful links

General Publications

• Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. doi: 10.1056/NEJMra0805786. No abstract available.
• Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009 Aug;137(2):541-8. doi: 10.1053/j.gastro.2009.04.062. Epub 2009 May 13.
• Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007 Jun;45(6):1348-54. doi: 10.1002/hep.21607.
• Mathurin P. Corticosteroids for alcoholic hepatitis--what's next? J Hepatol. 2005 Sep;43(3):526-33. doi: 10.1016/j.jhep.2005.06.003. No abstract available.
• Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D; Foie-Alcool group of the Association Francaise pour l'Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004 May;39(5):1390-7. doi: 10.1002/hep.20206.
• Mathurin P, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, Valla D, Poupon R, Chaput JC, Naveau S. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003 Dec;38(6):1363-9. doi: 10.1016/j.hep.2003.09.038.
• Mathurin P, Mendenhall CL, Carithers RL Jr, Ramond MJ, Maddrey WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002 Apr;36(4):480-7. doi: 10.1016/s0168-8278(01)00289-6.
• Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, Chaput JC, Rueff B, Poynard T. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology. 1996 Jun;110(6):1847-53. doi: 10.1053/gast.1996.v110.pm8964410.
• Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med. 1992 Feb 20;326(8):507-12. doi: 10.1056/NEJM199202203260802.
• Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA. 2013 Sep 11;310(10):1033-41. doi: 10.1001/jama.2013.276300.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): January 1, 2011

Study Registration Dates

• First Submitted: October 1, 2010
• First Submitted That Met QC Criteria: October 1, 2010
• First Posted (Estimate): October 4, 2010

Study Record Updates

• Last Update Posted (Estimate): June 1, 2011
• Last Update Submitted That Met QC Criteria: May 31, 2011
• Last Verified: September 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Digestive System Diseases; Alcohol-Related Disorders; Substance-Related Disorders; RNA Virus Infections; Virus Diseases; Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Alcohol-Induced Disorders; Liver Diseases; Hepatitis; Hepatitis A; Hepatitis, Alcoholic; Liver Diseases, Alcoholic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: 2006-006944-78 (EudraCT Number); PROM 2006/0636 (Other Identifier: CHRU de Lille - promoteur)