Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Alcoholic Hepatitis, Alcoholic Liver Disease

Intervention / Treatment
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* Drug: Pentoxifylline
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 |