Alcoholic Hepatitis, Alcoholic Liver Disease
Conditions
Keywords
Alcoholic hepatitis, corticotherapy, antibiotherapy, survival, infection, hepato renal syndrome
Brief summary
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
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).
Interventions
DRUGAmoxicillin
Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days
DRUGPlacebo
Placebo in three daily doses during 30 days
DRUGPrednisolone
Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days
Sponsors
Ministry of Health, France
University Hospital, Lille
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patient alive | at day 60 | The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Infection | at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months | incidence of infection over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm |
| Hepatorenal syndrome | at day 7, day14, day 21, day 30,at 3 months, at 6 months | incidence of hepatorenal syndrome over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm |
| MELD score <17 | at day 7, day14, day 21, day 30, | 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. |
| Lille Model | at day 7, after the first administration of treatment | percentage of patients disclosing a response to treatment assessed by the Lille model (\<0.45) in the two arms of treatment. |
| Patient alive | at 3 months, at 6 months | The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm |
Countries
France
Outcome results
None listed