Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis - Full Text View

Purpose

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.

Condition	Intervention	Phase
Alcoholic Hepatitis Alcoholic Liver Disease	Drug: Pentoxifylline Drug: placebo	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Evaluation of the Survival Benefit of the Adjunction of Pentoxifylline to Corticosteroids in Patients Suffering From Severe Alcoholic Hepatitis

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Liver Diseases Steroids

Drug Information available for: Prednisolone Prednisolone acetate Methylprednisolone acetate Methylprednisolone Prednisolone sodium phosphate Prednisolone phosphate Prednisolone sodium succinate Methylprednisolone sodium succinate Pentoxifylline

U.S. FDA Resources

Further study details as provided by University Hospital, Lille:

Primary Outcome Measures:

Overall Survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Hepatorenal syndrome [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Score of Lille model [ Time Frame: Seven days ] [ Designated as safety issue: No ]
Percentage of Meld score (Model for End-stage Liver Disease) higher than 17 [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment:	278
Study Start Date:	December 2007
Study Completion Date:	January 2011
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: TORENTAL 400MG

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.

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01214226

Locations

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

Sponsors and Collaborators

University Hospital, Lille

Ministry of Health, France

Investigators

Principal Investigator:

Philippe MATHURIN, MD PhD

University Hospital, Lille

More Information

Publications:

Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. Review. 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. 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.

Mathurin P. Corticosteroids for alcoholic hepatitis--what's next? J Hepatol. 2005 Sep;43(3):526-33. Review. No abstract available.

Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D; Foie-Alcool group of the Association Française 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.

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.

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.

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.

Ramond MJ, Poynard T, Rueff B, Mathurin P, Théodore 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.

Responsible Party:	Service des Maladies de l'Appareil Digestif, Hôpital Huriez,, CHRU Lille, France (Pr Philippe Mathurin / MD, PhD)
ClinicalTrials.gov Identifier:	NCT01214226 History of Changes
Other Study ID Numbers:	2006-006944-78, PROM 2006/0636, 2006-006944-78
Study First Received:	October 1, 2010
Last Updated:	May 31, 2011
Health Authority:	France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:

Hepatitis, Alcoholic
Hepatitis
Hepatitis A
Liver Diseases
Liver Diseases, Alcoholic
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Prednisolone

Pentoxifylline
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Hematologic Agents

ClinicalTrials.gov processed this record on May 16, 2013

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