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Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone (AntibioCor)

Primary Purpose

Alcoholic Hepatitis, Alcoholic Liver Disease

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Amoxicillin
Placebo
Prednisolone
Sponsored by
University Hospital, Lille
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis focused on measuring Alcoholic hepatitis, corticotherapy, antibiotherapy, survival, infection, hepato renal syndrome

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • CHU d'Amiens
  • CHU
  • CHU de Besançon
  • Hôpital Jean Verdier (AH-HP)
  • CHU de Caen
  • Hôpital BEaujon (AP-HP)
  • Centre hospitalier
  • CHU Grenoble
  • Hôpital Claude Huriez, CHU
  • CHU Montpellier
  • CHU Nantes
  • CHU Nice
  • Hôpital Saint Antoine (AP-HP)
  • Hôpital La Pitié (AP-HP)
  • CHU Poitiers
  • CHU Pontchaillou
  • CHU
  • CHU
  • Centre Hospitalier
  • Hôpital Paul Brousse (AH-HP)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

amoxicillin+ prednisolone

Placebo + prednisolone

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Infection
incidence of infection over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm
Hepatorenal syndrome
incidence of hepatorenal syndrome over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm
MELD score <17
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
percentage of patients disclosing a response to treatment assessed by the Lille model (<0.45) in the two arms of treatment.
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

Full Information

First Posted
October 28, 2014
Last Updated
March 24, 2021
Sponsor
University Hospital, Lille
Collaborators
Ministry of Health, France
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1. Study Identification

Unique Protocol Identification Number
NCT02281929
Brief Title
Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone
Acronym
AntibioCor
Official Title
Evaluation of the Efficacy of an Antibiotic Combined With Standard Treatment in Severe Alcoholic Hepatitis
Study Type
Interventional

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
June 13, 2015 (Actual)
Primary Completion Date
November 19, 2019 (Actual)
Study Completion Date
November 19, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Lille
Collaborators
Ministry of Health, France

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis, Alcoholic Liver Disease
Keywords
Alcoholic hepatitis, corticotherapy, antibiotherapy, survival, infection, hepato renal syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
297 (Actual)

8. Arms, Groups, and Interventions

Arm Title
amoxicillin+ prednisolone
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Placebo + prednisolone
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Amoxicillin
Other Intervention Name(s)
Amoxicillin + clavulanic acid
Intervention Description
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
Intervention Name(s)
Placebo
Other Intervention Name(s)
Placebo of amoxicillin
Intervention Description
Placebo in three daily doses during 30 days
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Other Intervention Name(s)
corticotherapy
Intervention Description
Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days
Primary Outcome Measure Information:
Title
Patient alive
Description
The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm
Time Frame
at day 60
Secondary Outcome Measure Information:
Title
Infection
Description
incidence of infection over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm
Time Frame
at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months
Title
Hepatorenal syndrome
Description
incidence of hepatorenal syndrome over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm
Time Frame
at day 7, day14, day 21, day 30,at 3 months, at 6 months
Title
MELD score <17
Description
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.
Time Frame
at day 7, day14, day 21, day 30,
Title
Lille Model
Description
percentage of patients disclosing a response to treatment assessed by the Lille model (<0.45) in the two arms of treatment.
Time Frame
at day 7, after the first administration of treatment
Title
Patient alive
Description
The percentage of patients alive at 2 months in the experimental arm compared to the percentage of patients alive in the control arm
Time Frame
at 3 months, at 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mathurin Philippe, MD,PhD
Organizational Affiliation
University Hospital, Lille
Official's Role
Study Chair
Facility Information:
Facility Name
CHU d'Amiens
City
Amiens
Country
France
Facility Name
CHU
City
Angers
Country
France
Facility Name
CHU de Besançon
City
Besançon
Country
France
Facility Name
Hôpital Jean Verdier (AH-HP)
City
Bondy
ZIP/Postal Code
93143
Country
France
Facility Name
CHU de Caen
City
Caen
Country
France
Facility Name
Hôpital BEaujon (AP-HP)
City
Clichy
Country
France
Facility Name
Centre hospitalier
City
Dunkerque
Country
France
Facility Name
CHU Grenoble
City
Grenoble
Country
France
Facility Name
Hôpital Claude Huriez, CHU
City
Lille
Country
France
Facility Name
CHU Montpellier
City
Montpellier
Country
France
Facility Name
CHU Nantes
City
Nantes
Country
France
Facility Name
CHU Nice
City
Nice
Country
France
Facility Name
Hôpital Saint Antoine (AP-HP)
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Hôpital La Pitié (AP-HP)
City
Paris
Country
France
Facility Name
CHU Poitiers
City
Poitiers
Country
France
Facility Name
CHU Pontchaillou
City
Rennes
Country
France
Facility Name
CHU
City
Rouen
Country
France
Facility Name
CHU
City
Toulouse
Country
France
Facility Name
Centre Hospitalier
City
Valenciennes
ZIP/Postal Code
59300
Country
France
Facility Name
Hôpital Paul Brousse (AH-HP)
City
Villejuif
ZIP/Postal Code
94000
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
20940288
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.
Results Reference
background
PubMed Identifier
22070475
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.
Results Reference
background
PubMed Identifier
19553649
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.
Results Reference
background
PubMed Identifier
19445945
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.
Results Reference
background
PubMed Identifier
17518367
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.
Results Reference
background
PubMed Identifier
24026598
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.
Results Reference
background
Links:
URL
http://www.lillemodel.com/
Description
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Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone

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