Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone
- Conditions
- Alcoholic HepatitisAlcoholic Liver Disease
- Interventions
- Registration Number
- NCT02281929
- Lead Sponsor
- University Hospital, Lille
- 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).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 297
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo + prednisolone Placebo 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. amoxicillin+ prednisolone Amoxicillin 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. amoxicillin+ prednisolone Prednisolone 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. Placebo + prednisolone Prednisolone 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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
Trial Locations
- Locations (18)
Centre hospitalier
🇫🇷Dunkerque, France
CHU de Besançon
🇫🇷Besançon, France
CHU d'Amiens
🇫🇷Amiens, France
CHU
🇫🇷Toulouse, France
Hôpital BEaujon (AP-HP)
🇫🇷Clichy, France
Hôpital Claude Huriez, CHU
🇫🇷Lille, France
Hôpital Jean Verdier (AH-HP)
🇫🇷Bondy, France
CHU de Caen
🇫🇷Caen, France
CHU Grenoble
🇫🇷Grenoble, France
CHU Montpellier
🇫🇷Montpellier, France
Hôpital Saint Antoine (AP-HP)
🇫🇷Paris, France
Hôpital La Pitié (AP-HP)
🇫🇷Paris, France
CHU Nantes
🇫🇷Nantes, France
CHU Pontchaillou
🇫🇷Rennes, France
Centre Hospitalier
🇫🇷Valenciennes, France
CHU Nice
🇫🇷Nice, France
CHU Poitiers
🇫🇷Poitiers, France
Hôpital Paul Brousse (AH-HP)
🇫🇷Villejuif, France