Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone

NCT02281929 | Completed Phase 3 DMC

• 3 other identifiers: 2014_052014-002536-13PHRC-2013-0552
• Study Type: interventional
• Target: 297
• Locations: 1 country
• Sites: 20

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.

Conditions

Alcoholic Hepatitis; Alcoholic Liver Disease

Keywords

Alcoholic hepatitis; corticotherapy; antibiotherapy; survival; infection; hepato renal syndrome

Outcome Measures

Primary Outcomes (1)

• Patient alive

  The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm

  at day 60

Secondary Outcomes (5)

• Infection

  at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months

• Hepatorenal syndrome

  at day 7, day14, day 21, day 30,at 3 months, at 6 months

• MELD score <17

  at day 7, day14, day 21, day 30,

• Lille Model

  at day 7, after the first administration of treatment

• Patient alive

  at 3 months, at 6 months

Study Arms (2)

amoxicillin+ prednisolone

ACTIVE COMPARATOR

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.

Drug: Amoxicillin; Drug: Prednisolone

Placebo + prednisolone

PLACEBO COMPARATOR

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.

Drug: Placebo; Drug: Prednisolone

Interventions

Amoxicillin DRUG

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

Also known as: Amoxicillin + clavulanic acid

amoxicillin+ prednisolone

Placebo DRUG

Placebo in three daily doses during 30 days

Also known as: Placebo of amoxicillin

Placebo + prednisolone

Prednisolone DRUG

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

Also known as: corticotherapy

Placebo + prednisolone; amoxicillin+ prednisolone

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital, Lille: lead
• Ministry of Health, France: collaborator

Study Sites (20)

CHU d'Amiens

Amiens, France

Location

CHU

Angers, France

Location

CHU de Besançon

Besançon, France

Location

Hôpital Jean Verdier (AH-HP)

Bondy, 93143, France

Location

CHU de Caen

Caen, France

Location

Hôpital BEaujon (AP-HP)

Clichy, France

Location

Centre hospitalier

Dunkirk, France

Location

CHU Grenoble

Grenoble, France

Location

Hôpital Claude Huriez, CHU

Lille, France

Location

CHU Montpellier

Montpellier, France

Location

CHU Nantes

Nantes, France

Location

CHU Nice

Nice, France

Location

Hôpital Saint Antoine (AP-HP)

Paris, 75012, France

Location

Hôpital La Pitié (AP-HP)

Paris, France

Location

CHU Poitiers

Poitiers, France

Location

CHU Pontchaillou

Rennes, France

Location

CHU

Rouen, France

Location

CHU

Toulouse, France

Location

Centre Hospitalier

Valenciennes, 59300, France

Location

Hôpital Paul Brousse (AH-HP)

Villejuif, 94000, France

Location

Related Publications (7)

• 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.

  PMID: 20940288 BACKGROUND

• 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.

  PMID: 22070475 BACKGROUND

• 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.

  PMID: 19553649 BACKGROUND

• 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.

  PMID: 19445945 BACKGROUND

• 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.

  PMID: 17518367 BACKGROUND

• 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.

  PMID: 24026598 BACKGROUND

• 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.

  PMID: 37159035 RESULT

Related Links

• Related Info

MeSH Terms

Conditions

Hepatitis, Alcoholic; Liver Diseases, Alcoholic; Infections; Hepatorenal Syndrome

Interventions

Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Prednisolone

Condition Hierarchy (Ancestors)

Hepatitis; Liver Diseases; Digestive System Diseases; Alcohol-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Ampicillin; Penicillin G; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Clavulanic Acid; Clavulanic Acids; Drug Combinations; Pharmaceutical Preparations; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Mathurin Philippe, MD,PhD

  University Hospital, Lille

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2014
• First Posted: November 4, 2014
• Study Start: June 13, 2015
• Primary Completion: November 19, 2019
• Study Completion: November 19, 2019
• Last Updated: December 22, 2025

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (20)