Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis

Phase 3

Completed

• Conditions: Alcoholic Hepatitis; Alcoholic Liver Disease
• Interventions: Drug: placebo; Drug: Pentoxifylline

• Registration Number: NCT01214226
• Lead Sponsor: University Hospital, Lille

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.

Study Timeline

• Study Start: 2007-12
• Status Verified: 2010-09
• Study First Submitted: 2010-10-01
• Study First Submitted QC: 2010-10-01
• Study First Posted: 2010-10-04
• Primary Completion: 2010-12
• Study Completion: 2011-01
• Last Update Submitted: 2011-05-31
• Last Update Posted: 2011-06-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 278

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Pentoxifylline + Prednisolone	placebo	Pentoxifylline 400 mg prolonged-released tablets 3 time a day \[1200 mg/day\] + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY \[40 mg/day\]
Placebo + Prednisolone	Pentoxifylline	Placebo prolonged-release tabled 3 time a day + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY \[40 mg/day\]

Primary Outcome Measures

Name	Time	Method
Overall Survival	6 months

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (15)

University hospital; 🇫🇷 Rennes, France

Hôpital Jean Verdier (AH-HP); 🇫🇷 Bondy, France

Centre hospitalier; 🇫🇷 Dunkerque, France

Hôpital Beaujon (AH-HP); 🇫🇷 Clichy, France

Hôpital Henri Mondor (AP-HP); 🇫🇷 Créteil, France

Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris); 🇫🇷 Clamart, France

Hôpital Saint Antoine (AP-HP); 🇫🇷 Paris, France

Centre Hospitalier; 🇫🇷 Valenciennes, France

Centre hospitalier Sambre en avesnois; 🇫🇷 Maubeuge, France

Hôpital de la Pitié-Salpétrière (AP-HP); 🇫🇷 Paris, France

Hôpital Cochin (AH-HP); 🇫🇷 Paris, France

Centre Hospitalier Victor Provo; 🇫🇷 Roubaix, France

University Hospital; 🇫🇷 Strasbourg, France

University hospital, Nancy; 🇫🇷 Vandoeuvre les nancy, France

Hôpital Paul Brousse (AH-HP); 🇫🇷 Villejuif, France