Efficacy of Antibiotic Therapy in Severe Alcoholic Hepatitis Treated With Prednisolone

Alcoholic Hepatitis Clinical Trial

— AntibioCor  

Official title:

Evaluation of the Efficacy of an Antibiotic Combined With Standard Treatment in Severe Alcoholic Hepatitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02281929
• Other study ID #: 2014_05
• Secondary ID: 2014-002536-13PH
• Status: Completed
• Phase: Phase 3
• Start date: June 13, 2015
• Est. completion date: November 19, 2019

Study information

• Verified date: March 2021
• Source: University Hospital, Lille
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 297
• Est. completion date: November 19, 2019
• Est. primary completion date: November 19, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Alcoholic Hepatitis
• Alcoholic Liver Disease
• Hepatitis
• Hepatitis A
• Hepatitis, Alcoholic
• Liver Diseases
• Liver Diseases, Alcoholic

Intervention

Drug:
• Amoxicillin
Amoxicillin+clavulanic acid at a daily dose of 3 gram / 375 mg in three daily doses of 1g/125mg, during 30 days
• Placebo
Placebo in three daily doses during 30 days
• Prednisolone
Prednisolone at 40 mg/j in a single daily dose in the morning, during 30 days

Locations

Country	Name	City	State
France	CHU d'Amiens	Amiens
France	CHU	Angers
France	CHU de Besançon	Besançon
France	Hôpital Jean Verdier (AH-HP)	Bondy
France	CHU de Caen	Caen
France	Hôpital BEaujon (AP-HP)	Clichy
France	Centre hospitalier	Dunkerque
France	CHU Grenoble	Grenoble
France	Hôpital Claude Huriez, CHU	Lille
France	CHU Montpellier	Montpellier
France	CHU Nantes	Nantes
France	CHU Nice	Nice
France	Hôpital La Pitié (AP-HP)	Paris
France	Hôpital Saint Antoine (AP-HP)	Paris
France	CHU Poitiers	Poitiers
France	CHU Pontchaillou	Rennes
France	CHU	Rouen
France	CHU	Toulouse
France	Centre Hospitalier	Valenciennes
France	Hôpital Paul Brousse (AH-HP)	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Lille	Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (6)

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. — View 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. — View Citation

Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009 Jun 25;360(26):2758-69. doi: 10.1056/NEJMra0805786. Review. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Infection	incidence of infection over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm	at day 7, day14, day 21, day 30, day 60; at 3 months, at 6 months
Secondary	Hepatorenal syndrome	incidence of hepatorenal syndrome over the 2-month period in the antibiotic+corticosteroid arm as compared to the control arm	at day 7, day14, day 21, day 30,at 3 months, at 6 months
Secondary	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.	at day 7, day14, day 21, day 30,
Secondary	Lille Model	percentage of patients disclosing a response to treatment assessed by the Lille model (<0.45) in the two arms of treatment.	at day 7, after the first administration of treatment
Secondary	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 3 months, at 6 months

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