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

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ClinicalTrials.gov Identifier: NCT02281929
Recruitment Status : Recruiting
First Posted : November 4, 2014
Last Update Posted : April 24, 2018
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Alcoholic Liver Disease Drug: Amoxicillin Drug: Placebo Drug: Prednisolone Phase 3

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).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluation of the Efficacy of an Antibiotic Combined With Standard Treatment in Severe Alcoholic Hepatitis
Actual Study Start Date : June 13, 2015
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Active Comparator: 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.
Drug: Amoxicillin
Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days
Other Name: Amoxicillin + clavulanic acid

Drug: Prednisolone
Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days
Other Name: corticotherapy

Placebo Comparator: 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.
Drug: Placebo
Placebo in three daily doses during 30 days
Other Name: Placebo of amoxicillin

Drug: Prednisolone
Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days
Other Name: corticotherapy




Primary Outcome Measures :
  1. Patient alive [ Time Frame: 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 :
  1. Infection [ Time Frame: 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

  2. Hepatorenal syndrome [ Time Frame: 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

  3. MELD score <17 [ Time Frame: 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.

  4. Lille Model [ Time Frame: 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.

  5. Patient alive [ Time Frame: 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



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02281929


Contacts
Contact: Mathurin Philippe, MD,PhD phillippe.mathurin@chru-lille.fr
Contact: Louvet Alexandre, MD,PhD alexandre.louvet@chru-lille.fr

Locations
France
CHU d'Amiens Recruiting
Amiens, France
Principal Investigator: Eric N'Guyen khac, MD,PhD         
CHU Recruiting
Angers, France
Principal Investigator: François Oberti, MD,PhD         
CHU de Besançon Recruiting
Besançon, France
Principal Investigator: Thierry Thevenot, MD,         
Hôpital Jean Verdier (AH-HP) Recruiting
Bondy, France, 93143
Contact: Pierre Nahon, MD         
Principal Investigator: pierre Nahon, MD         
CHU de Caen Recruiting
Caen, France
Principal Investigator: Thong DAO, MD,PhD         
Hôpital BEaujon (AP-HP) Recruiting
Clichy, France
Principal Investigator: A Payance, MD         
Centre hospitalier Recruiting
Dunkerque, France
Principal Investigator: thierry Paupard, MD         
CHU Grenoble Recruiting
Grenoble, France
Principal Investigator: Vincent Leroy, MD         
Hôpital Claude Huriez, CHU Recruiting
Lille, France
Contact: Alexandre Louvet, MD,PhD         
Principal Investigator: Philippe Mathurin, MD,PhD         
Sub-Investigator: Alexandre Louvet, MD, PhD         
CHU Montpellier Recruiting
Montpellier, France
Principal Investigator: Georges Pageaux, Md,PhD         
CHU Nantes Recruiting
Nantes, France
Principal Investigator: J Gournay, MD,PhD         
CHU Nice Recruiting
Nice, France
Principal Investigator: Rodolphe Anty, MD         
Hôpital Saint Antoine (AP-HP) Recruiting
Paris, France, 75012
Contact: Nicolas Carbonell, MD         
Principal Investigator: Nicolas Carbonell, MD         
Hôpital La Pitié (AP-HP) Recruiting
Paris, France
Principal Investigator: Dominique Thabut, MD         
CHU Poitiers Recruiting
Poitiers, France
Principal Investigator: Christine Sylvain, MD,PhD         
CHU Pontchaillou Recruiting
Rennes, France
Principal Investigator: L Legros, MD         
CHU Recruiting
Rouen, France
Principal Investigator: O Goria, MD         
CHU Recruiting
Toulouse, France
Principal Investigator: Chritophe Bureau, MD         
Centre Hospitalier Recruiting
Valenciennes, France, 59300
Contact: Faustine Wartel, MD         
Principal Investigator: Faustine Wartel, MD         
Hôpital Paul Brousse (AH-HP) Not yet recruiting
Villejuif, France, 94000
Contact: J-C Duclos-Vallée         
Principal Investigator: J-C Duclos-Vallée, MD PhD         
Sponsors and Collaborators
University Hospital, Lille
Ministry of Health, France
Investigators
Study Chair: Mathurin Philippe, MD,PhD University Hospital, Lille

Additional Information:
Publications:

Responsible Party: University Hospital, Lille
ClinicalTrials.gov Identifier: NCT02281929     History of Changes
Other Study ID Numbers: 2014_05
2014-002536-13 ( EudraCT Number )
PHRC-2013-0552 ( Other Identifier: Minister of Health, France )
First Posted: November 4, 2014    Key Record Dates
Last Update Posted: April 24, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by University Hospital, Lille:
Alcoholic hepatitis
corticotherapy
antibiotherapy
survival
infection
hepato renal syndrome

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Liver Diseases
Hepatitis, Alcoholic
Liver Diseases, Alcoholic
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Anti-Bacterial Agents
Amoxicillin
Clavulanic Acids
Clavulanic Acid
Amoxicillin-Potassium Clavulanate Combination
Prednisolone acetate
Methylprednisolone acetate
Prednisolone
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Infective Agents
Anti-Inflammatory Agents
Glucocorticoids