Clinical trial NCT01214226: Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis
Official title: Evaluation of the Survival Benefit of the Adjunction of Pentoxifylline to Corticosteroids in Patients Suffering From Severe Alcoholic Hepatitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alcoholic Hepatitis
Alcoholic Liver Disease
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2010-10-04
Enrollment: 278
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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

Primary outcomes:
measure: Overall Survival
timeFrame: 6 months
Secondary outcomes:
measure: Hepatorenal syndrome
timeFrame: 6 months
measure: Score of Lille model
timeFrame: Seven days
measure: Percentage of Meld score (Model for End-stage Liver Disease) higher than 17
timeFrame: 6 months
Other outcomes:
Locations:
city: Brussel
country: Belgium
facility: University hospital
city: Angers
country: France
facility: University hospital
city: Bondy
country: France
facility: Hôpital Jean Verdier (AH-HP)
city: Bordeaux
country: France
facility: University hospital
city: Béthune
country: France
facility: Centre hospitalier
city: Caen
country: France
facility: University hospital
city: Clamart
country: France
facility: Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)
city: Clichy
country: France
facility: Hôpital Beaujon (AH-HP)
city: Creil
country: France
facility: Centre Hospitalier
city: Créteil
country: France
facility: Hôpital Henri Mondor (AP-HP)
city: Dunkerque
country: France
facility: Centre hospitalier
city: Lens
country: France
facility: Centre Hospitalier
city: Lille
country: France
facility: University hospital
city: Maubeuge
country: France
facility: Centre hospitalier Sambre en avesnois
city: Montpellier
country: France
facility: University hospital
city: Nantes
country: France
facility: University hospital
city: Nice
country: France
facility: University hospital
city: Paris
country: France
facility: Hôpital Saint Antoine (AP-HP)
city: Paris
country: France
facility: Hôpital de la Pitié-Salpétrière (AP-HP)
city: Paris
country: France
facility: Hôpital Cochin (AH-HP)
city: Poitiers
country: France
facility: University hospital
city: Rennes
country: France
facility: University hospital
city: Roubaix
country: France
facility: Centre Hospitalier Victor Provo
city: Strasbourg
country: France
facility: University Hospital
city: Tourcoing
country: France
facility: Centre Hospitalier
city: Valenciennes
country: France
facility: Centre Hospitalier
city: Vandoeuvre les nancy
country: France
facility: University hospital, Nancy
city: Villejuif
country: France
facility: Hôpital Paul Brousse (AH-HP)
Study officials:
affiliation: University Hospital, Lille
name: Philippe MATHURIN, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.