Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone (AntibioCor)

University Hospital, Lille

Status and phase: Completed; Phase 3

Conditions: Alcoholic Liver Disease; Alcoholic Hepatitis

Treatments: Drug: Prednisolone; Drug: Placebo; Drug: Amoxicillin

Study type: Interventional

Funder types: Other

Identifiers

NCT02281929

2014_05

PHRC-2013-0552 (Other Identifier)

2014-002536-13 (EudraCT Number)

Details and patient eligibility

About

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.

Full description

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).

Enrollment: 297 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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297 participants in 2 patient groups, including a placebo group

amoxicillin+ prednisolone

Active Comparator group

Description:

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.

Treatment:

Drug: Amoxicillin

Drug: Prednisolone

Placebo + prednisolone

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: Prednisolone