Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone

Study Overview
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Brief Summary
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Treatment of reference of severe alcoholic hepatitis is based on corticosteroids, given for 28 days. However, about 25-35% of patients do not take benefit from this treatment and die within the 6 months following the diagnosis. Numerous trials have evaluated the impact of several strategies in association with corticosteroids. None of them has shown an improvement in survival (primary endpoint) as compared to corticosteroids alone. The project is based on an approach never tested in a randomized controlled trial in severe alcoholic hepatitis, targeting the group of patients at high risk of death (25-35% at 2 months). This approach is based on animal and human studies.Antibiotics are effective in animal models and in other circumstances characterized by liver failure such as gastrointestinal bleeding related to portal hypertension. The interest of studying this population is emphasized by the frequency of infections in these critically ill patients. Antibiotics will be administered before the development of any infection, as it is likely that these patients present with mesenteric bacterial adenitis without systemic signs of infection. Primary endpoint will be 2-month survival as most deaths occur within 60 days and treatment is given for 30 days.

Detailed Description
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This is a multicenter double-blind randomized controlled study on two parallel groups. Once inclusion and exclusion criteria verified and after having obtained patient written consent, participative centers will process to inclusion in the trial. Corticosteroids as well as antibiotics or their placebo will be started orally. Patients will be managed in the hospital unit until day 7, which corresponds to the evaluation of response to treatment using the Lille model. After this 7-day period, patients will be followed-up at day 14, day 21, day 30, day 60 (primary endpoint). During each visit, biological and clinical features including efficacy and tolerance will be assessed as well as presence of infection and hepatorenal syndrome (secondary endpoints).

Official Title
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Evaluation of the Efficacy of an Antibiotic Combined With Standard Treatment in Severe Alcoholic Hepatitis

Conditions
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Alcoholic Hepatitis, Alcoholic Liver Disease

Intervention / Treatment
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* Drug: Amoxicillin
* Drug: Placebo
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18-75 Recent onset of jaundice (<3 months) Biopsy proven alcoholic hepatitis (transjugular liver biopsy) Maddrey's discriminant function ≥ 32, defining severe alcoholic hepatitis MELD score ≥21 Alcohol consumption ≥ 40g/day (women) and ≥ 50g/day (men) Written informed consent Exclusion Criteria: Previous severe allergy or hypersensitivity to amoxicillin or clavulanic acid (anaphylactic shock, Quincke edema, severe urticaria) Hypersensitivity to any component of the medication History of liver injury to amoxicillin and/or clavulanic acid Phenylketonuria, because of the presence of aspartame in the powder for the oral suspension Type 1 hepatorenal syndrome before the initiation of treatment Severe extrahepatic disease Any malignant tumor < 2 years Uncontrolled gastrointestinal bleeding Ongoing viral or parasitic infection Untreated bacterial infection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: amoxicillin+ prednisolone<br>Oral antibiotherapy during 30 days using amoxicillin+clavulanic acid at a daily dose of 3 gram (amoxicillin) and 375 mg (clavulanic acid) in three daily doses of 1g/125mg. Oral corticotherapy during 30 days with prednisolone at 40 mg/j in a single daily dose in the morning. | Drug: Amoxicillin<br>* Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days<br>* Other names: Amoxicillin + clavulanic acid;Drug: Prednisolone<br>* Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days<br>* Other names: corticotherapy;|
| Placebo Comparator: Placebo + prednisolone<br>Oral placebo of amoxicillin- clavulanic acid in three daily doses during 30 days Oral corticotherapy during 30 days with prednisolone at 40 mg/j in a single daily dose in the morning. | Drug: Placebo<br>* Placebo in three daily doses during 30 days<br>* Other names: Placebo of amoxicillin;Drug: Prednisolone<br>* Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days<br>* Other names: corticotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient alive | The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm | at day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infection | incidence of infection over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm | at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months | 
| Hepatorenal syndrome | incidence of hepatorenal syndrome over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm | at day 7, day14, day 21, day 30,at 3 months, at 6 months | 
| MELD score <17 | percentage of patients with a low risk of mortality during the first two months (assessed by a MELD score <17) in the two arms of treatment. The MELD score will be calculated using the following formula:(9.57 × log creatinine in milligrams per deciliter) + (3.78 × log bilirubin in milligrams per deciliter) + (11.20 × log international normalized ratio) + 6.43. | at day 7, day14, day 21, day 30, | 
| Lille Model | percentage of patients disclosing a response to treatment assessed by the Lille model (<0.45) in the two arms of treatment. | at day 7, after the first administration of treatment | 
| Patient alive | The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm | at 3 months, at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcoholic hepatitis, corticotherapy, antibiotherapy, survival, infection, hepato renal syndrome