Clinical trial NCT02281929: Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone
Official title: Evaluation of the Efficacy of an Antibiotic Combined With Standard Treatment in Severe Alcoholic Hepatitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alcoholic Hepatitis
Alcoholic Liver Disease
Keywords: Alcoholic hepatitis
corticotherapy
antibiotherapy
survival
infection
hepato renal syndrome
Lead sponsor: University Hospital, Lille
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2014-11-04
Enrollment: 297
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Patient alive
timeFrame: at day 60
Secondary outcomes:
measure: Infection
timeFrame: at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months
measure: Hepatorenal syndrome
timeFrame: at day 7, day14, day 21, day 30,at 3 months, at 6 months
measure: MELD score <17
timeFrame: at day 7, day14, day 21, day 30,
measure: Lille Model
timeFrame: at day 7, after the first administration of treatment
measure: Patient alive
timeFrame: at 3 months, at 6 months
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU d'Amiens
city: Angers
country: France
facility: CHU
city: Besançon
country: France
facility: CHU de Besançon
city: Bondy
country: France
facility: Hôpital Jean Verdier (AH-HP)
city: Caen
country: France
facility: CHU de Caen
city: Clichy
country: France
facility: Hôpital BEaujon (AP-HP)
city: Dunkerque
country: France
facility: Centre hospitalier
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: Hôpital Claude Huriez, CHU
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Hôpital Saint Antoine (AP-HP)
city: Paris
country: France
facility: Hôpital La Pitié (AP-HP)
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU Pontchaillou
city: Rouen
country: France
facility: CHU
city: Toulouse
country: France
facility: CHU
city: Valenciennes
country: France
facility: Centre Hospitalier
city: Villejuif
country: France
facility: Hôpital Paul Brousse (AH-HP)
Study officials:
affiliation: University Hospital, Lille
name: Mathurin Philippe, MD,PhD
role: STUDY_CHAIR
References:
citation: Mathurin P, O'Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011 Feb;60(2):255-60. doi: 10.1136/gut.2010.224097. Epub 2010 Oct 12.
citation: Nguyen-Khac E, Thevenot T, Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL; AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011 Nov 10;365(19):1781-9. doi: 10.1056/NEJMoa1101214.
citation: Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. doi: 10.1056/NEJMra0805786. No abstract available.
citation: Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009 Aug;137(2):541-8. doi: 10.1053/j.gastro.2009.04.062. Epub 2009 May 13.
citation: Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007 Jun;45(6):1348-54. doi: 10.1002/hep.21607.
citation: Mathurin P, Louvet A, Duhamel A, Nahon P, Carbonell N, Boursier J, Anty R, Diaz E, Thabut D, Moirand R, Lebrec D, Moreno C, Talbodec N, Paupard T, Naveau S, Silvain C, Pageaux GP, Sobesky R, Canva-Delcambre V, Dharancy S, Salleron J, Dao T. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial. JAMA. 2013 Sep 11;310(10):1033-41. doi: 10.1001/jama.2013.276300.