Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis

Alcoholic Hepatitis Clinical Trial

— CorpentoxHAA  

Official title:

Evaluation of the Survival Benefit of the Adjunction of Pentoxifylline to Corticosteroids in Patients Suffering From Severe Alcoholic Hepatitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01214226
• Other study ID #: 2006-006944-78
• Secondary ID: PROM 2006/063620
• Status: Completed
• Phase: Phase 3
• First received: October 1, 2010
• Last updated: May 31, 2011
• Start date: December 2007
• Est. completion date: January 2011

Study information

• Verified date: September 2010
• Source: University Hospital, Lille
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial Summary

The treatment of severe forms of alcoholic hepatitis (AH) constitutes a major challenge for clinicians involved in the management of severe alcoholic liver disease. In patients with Maddrey function higher than 32, compelling evidence from data has shown that corticosteroids improve short-term survival. However, novel strategies or molecules are required in light of the fact that approximately 40 % of patients continue to die at 6 months. A double-blinded randomized controlled trial of 101 patients has showed that Pentoxifylline improves survival of patients with severe AH, as compared to placebo. In terms of mechanisms, the effect of pentoxifylline is related to prevention of hepatorenal function whereas corticosteroids induce an early improvement in liver function. When considering these differences of mechanisms, many clinicians suggest that the addition of pentoxyfilline to corticosteroids is an attractive option that needs to be tested in patients with severe AH.

Description:

The aim of the present study is to determine whether or not the adjunction of Pentoxifylline to corticosteroids would improve 6-month survival of patients with severe alcoholic hepatitis. This multicenter, randomized, double-blinded, controlled, phase 3 trial was conducted in 24 centers located in France and Belgium. Alcoholic hepatitis was biopsy-proven. All eligible patients were randomly assigned in a 1:1 ratio to receive corticosteroids + Pentoxifylline or corticosteroids + Placebo. The primary outcome of the study was 6-month survival. Assuming a two-sided type I error of 0.05, a randomization ratio of 1:1 between the 2 groups, 6-month survival of 64% in the Placebo and Corticosteroids group and of 78 % in the Pentoxifylline and Corticosteroids group, we estimated that with 268 randomized patients (134 in each group), the study would have a power of 80% to detect this increase in 6-month survival in the Pentoxifylline and Corticosteroid group.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 278
• Est. completion date: January 2011
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Alcohol consumption more than 40 gram/day for women and 50 gram/day for men

• Maddrey discriminant function higher than 32

• Onset of jaundice within the 3 previous months

• Biopsy-proven alcoholic hepatitis

Exclusion Criteria:

• Hypersensitivity to pentoxifylline

• Any severe disease that may potential affect survival such as cardiac failure, ischemic cardiopathy, respiratory failure

• Any neoplasm that occurred within the 2 previous years

• Hepatocellular carcinoma or any previous diagnosis of hepatocellular carcinoma

• Portal thrombosis

• Severe gastrointestinal bleeding

• Uncontrolled sepsis within the 7 previous days

• Hepatorenal syndrome type I

• Viral and fungal infection

• Acute pancreatitis

• Any tuberculosis that occurred within the 5 previous years

• Psychiatric disorders that contraindicate the use of corticosteroids

• Infection related to virus of the hepatites B or C

• HIV infection (Human immunodeficiency virus)

• Any treatment with corticosteroids, immunosuppressive agents, budesonide, thalidomide or pentoxifylline that was given within the previous year

• Pregnancy or breast feeding

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Pentoxifylline
400 mg prolonged-released tablets 3 time per day for 1 month.
• placebo
prolonged-release tablets 3 time per day for 1 month

Locations

Country	Name	City	State
Belgium	University hospital	Brussel
France	University hospital	Angers
France	Centre hospitalier	Béthune
France	Hôpital Jean Verdier (AH-HP)	Bondy
France	University hospital	Bordeaux
France	University hospital	Caen
France	Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)	Clamart
France	Hôpital Beaujon (AH-HP)	Clichy
France	Centre Hospitalier	Creil
France	Hôpital Henri Mondor (AP-HP)	Créteil
France	Centre hospitalier	Dunkerque
France	Centre Hospitalier	Lens
France	University hospital	Lille
France	Centre hospitalier Sambre en avesnois	Maubeuge
France	University hospital	Montpellier
France	University hospital	Nantes
France	University hospital	Nice
France	Hôpital Cochin (AH-HP)	Paris
France	Hôpital de la Pitié-Salpétrière (AP-HP)	Paris
France	Hôpital Saint Antoine (AP-HP)	Paris
France	University hospital	Poitiers
France	University hospital	Rennes
France	Centre Hospitalier Victor Provo	Roubaix
France	University Hospital	Strasbourg
France	Centre Hospitalier	Tourcoing
France	Centre Hospitalier	Valenciennes
France	University hospital, Nancy	Vandoeuvre les nancy
France	Hôpital Paul Brousse (AH-HP)	Villejuif

Sponsors (2)

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

Countries where clinical trial is conducted

Belgium,  France, 

References & Publications (9)

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 alcoholi — 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) — 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, Abdelnour M, Ramond MJ, Carbonell N, Fartoux L, Serfaty L, Valla D, Poupon R, Chaput JC, Naveau S. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003 Dec — View Citation

Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, Chaput JC, Rueff B, Poynard T. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology. 1996 Jun;110(6):1847 — View Citation

Mathurin P, Mendenhall CL, Carithers RL Jr, Ramond MJ, Maddrey WC, Garstide P, Rueff B, Naveau S, Chaput JC, Poynard T. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last thre — View Citation

Mathurin P. Corticosteroids for alcoholic hepatitis--what's next? J Hepatol. 2005 Sep;43(3):526-33. Review. — View Citation

Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D; Foie-Alcool group of the Association Française pour l'Etude du Foie. A double-blind randomized controlled trial of infliximab associated with pr — View Citation

Ramond MJ, Poynard T, Rueff B, Mathurin P, Théodore C, Chaput JC, Benhamou JP. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med. 1992 Feb 20;326(8):507-12. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		6 months	No
Secondary	Hepatorenal syndrome		6 months	No
Secondary	Score of Lille model		Seven days	No
Secondary	Percentage of Meld score (Model for End-stage Liver Disease) higher than 17		6 months	No