Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis

NCT01214226 | Completed Phase 3

• 2 other identifiers: 2006-006944-78PROM 2006/0636
• Study Type: interventional
• Target: 278
• Locations: 2 countries
• Sites: 28

Brief Summary

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.

Conditions

Alcoholic Hepatitis; Alcoholic Liver Disease

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  6 months

Secondary Outcomes (3)

• 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

Study Arms (2)

Pentoxifylline + Prednisolone

ACTIVE COMPARATOR

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

Placebo + Prednisolone

PLACEBO COMPARATOR

Placebo prolonged-release tabled 3 time a day \+ Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY \[40 mg/day\]

Drug: Pentoxifylline

Interventions

Pentoxifylline DRUG

400 mg prolonged-released tablets 3 time per day for 1 month.

Also known as: TORENTAL 400MG

Placebo + Prednisolone

placebo DRUG

prolonged-release tablets 3 time per day for 1 month

Pentoxifylline + Prednisolone

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Lille: lead
• Ministry of Health, France: collaborator

Study Sites (28)

University hospital

Brussels, 1070, Belgium

Location

University hospital

Angers, 49933, France

Location

Centre hospitalier

Béthune, 62408, France

Location

Hôpital Jean Verdier (AH-HP)

Bondy, 93143, France

Location

University hospital

Bordeaux, 33000, France

Location

University hospital

Caen, 14000, France

Location

Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)

Clamart, 92141, France

Location

Hôpital Beaujon (AH-HP)

Clichy, 92118, France

Location

Centre Hospitalier

Creil, 60100, France

Location

Hôpital Henri Mondor (AP-HP)

Créteil, 94000, France

Location

Centre hospitalier

Dunkirk, 59240, France

Location

Centre Hospitalier

Lens, 62300, France

Location

University hospital

Lille, 59037, France

Location

Centre hospitalier Sambre en avesnois

Maubeuge, 59600, France

Location

University hospital

Montpellier, 34295, France

Location

University hospital

Nantes, 45000, France

Location

University hospital

Nice, 06202, France

Location

Hôpital Saint Antoine (AP-HP)

Paris, 75012, France

Location

Hôpital de la Pitié-Salpétrière (AP-HP)

Paris, 75013, France

Location

Hôpital Cochin (AH-HP)

Paris, 75014, France

Location

University hospital

Poitiers, 49000, France

Location

University hospital

Rennes, 35033, France

Location

Centre Hospitalier Victor Provo

Roubaix, 59100, France

Location

University Hospital

Strasbourg, 67100, France

Location

Centre Hospitalier

Tourcoing, 59208, France

Location

Centre Hospitalier

Valenciennes, 59300, France

Location

University hospital, Nancy

Vandœuvre-lès-Nancy, 54511, France

Location

Hôpital Paul Brousse (AH-HP)

Villejuif, 94000, France

Location

Related Publications (10)

• 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.

  PMID: 19553649 RESULT

• 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.

  PMID: 19445945 RESULT

• 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.

  PMID: 17518367 RESULT

• 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.

  PMID: 16026887 RESULT

• 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.

  PMID: 15122768 RESULT

• 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.

  PMID: 14647046 RESULT

• 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.

  PMID: 11943418 RESULT

• 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.

  PMID: 8964410 RESULT

• 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.

  PMID: 1531090 RESULT

• 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.

  PMID: 24026598 DERIVED

MeSH Terms

Conditions

Hepatitis, Alcoholic; Liver Diseases, Alcoholic

Interventions

Pentoxifylline

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Theobromine; Xanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Philippe MATHURIN, MD PhD

  University Hospital, Lille

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: October 1, 2010
• First Posted: October 4, 2010
• Study Start: December 1, 2007
• Primary Completion: December 1, 2010
• Study Completion: January 1, 2011
• Last Updated: June 1, 2011

Record last verified: 2010-09

Locations

FR (27); BE (1)