Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone

NCT ID: NCT02281929

Last Updated: 2025-12-22

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

297 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-06-13

Study Completion Date

2019-11-19

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).

Conditions

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Alcoholic Hepatitis Alcoholic Liver Disease

Keywords

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Alcoholic hepatitis corticotherapy antibiotherapy survival infection hepato renal syndrome

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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amoxicillin+ 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.

Group Type ACTIVE_COMPARATOR

Amoxicillin

Intervention Type DRUG

Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days

Prednisolone

Intervention Type DRUG

Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days

Placebo + 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.

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo in three daily doses during 30 days

Prednisolone

Intervention Type DRUG

Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days

Interventions

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Amoxicillin

Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days

Intervention Type DRUG

Placebo

Placebo in three daily doses during 30 days

Intervention Type DRUG

Prednisolone

Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days

Intervention Type DRUG

Other Intervention Names

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Amoxicillin + clavulanic acid Placebo of amoxicillin corticotherapy

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.
Minimum Eligible Age

18 Years

Maximum Eligible Age

75 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Ministry of Health, France

OTHER_GOV

Sponsor Role collaborator

University Hospital, Lille

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Mathurin Philippe, MD,PhD

Role: STUDY_CHAIR

University Hospital, Lille

Locations

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CHU d'Amiens

Amiens, , France

Site Status

CHU

Angers, , France

Site Status

CHU de Besançon

Besançon, , France

Site Status

Hôpital Jean Verdier (AH-HP)

Bondy, , France

Site Status

CHU de Caen

Caen, , France

Site Status

Hôpital BEaujon (AP-HP)

Clichy, , France

Site Status

Centre hospitalier

Dunkirk, , France

Site Status

CHU Grenoble

Grenoble, , France

Site Status

Hôpital Claude Huriez, CHU

Lille, , France

Site Status

CHU Montpellier

Montpellier, , France

Site Status

CHU Nantes

Nantes, , France

Site Status

CHU Nice

Nice, , France

Site Status

Hôpital Saint Antoine (AP-HP)

Paris, , France

Site Status

Hôpital La Pitié (AP-HP)

Paris, , France

Site Status

CHU Poitiers

Poitiers, , France

Site Status

CHU Pontchaillou

Rennes, , France

Site Status

CHU

Rouen, , France

Site Status

CHU

Toulouse, , France

Site Status

Centre Hospitalier

Valenciennes, , France

Site Status

Hôpital Paul Brousse (AH-HP)

Villejuif, , France

Site Status

Countries

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France

References

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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.

Reference Type BACKGROUND
PMID: 20940288 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 22070475 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19553649 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19445945 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17518367 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24026598 (View on PubMed)

Louvet A, Labreuche J, Dao T, Thevenot T, Oberti F, Bureau C, Paupard T, Nguyen-Khac E, Minello A, Bernard-Chabert B, Anty R, Wartel F, Carbonell N, Pageaux GP, Hilleret MN, Moirand R, Nahon P, Potey C, Duhamel A, Mathurin P. Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis: A Randomized Clinical Trial. JAMA. 2023 May 9;329(18):1558-1566. doi: 10.1001/jama.2023.4902.

Reference Type RESULT
PMID: 37159035 (View on PubMed)

Related Links

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Other Identifiers

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2014-002536-13

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRC-2013-0552

Identifier Type: OTHER

Identifier Source: secondary_id

2014_05

Identifier Type: -

Identifier Source: org_study_id