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Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis (CorpentoxHAA)

Primary Purpose

Alcoholic Hepatitis, Alcoholic Liver Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Pentoxifylline
placebo
Sponsored by
University Hospital, Lille
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University hospital
  • University hospital
  • Hôpital Jean Verdier (AH-HP)
  • University hospital
  • Centre hospitalier
  • University hospital
  • Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)
  • Hôpital Beaujon (AH-HP)
  • Centre Hospitalier
  • Hôpital Henri Mondor (AP-HP)
  • Centre hospitalier
  • Centre Hospitalier
  • University hospital
  • Centre hospitalier Sambre en avesnois
  • University hospital
  • University hospital
  • University hospital
  • Hôpital Saint Antoine (AP-HP)
  • Hôpital de la Pitié-Salpétrière (AP-HP)
  • Hôpital Cochin (AH-HP)
  • University hospital
  • University hospital
  • Centre Hospitalier Victor Provo
  • University Hospital
  • Centre Hospitalier
  • Centre Hospitalier
  • University hospital, Nancy
  • Hôpital Paul Brousse (AH-HP)

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Pentoxifylline + Prednisolone

Placebo + Prednisolone

Arm Description

Pentoxifylline 400 mg prolonged-released tablets 3 time a day [1200 mg/day] + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]

Placebo prolonged-release tabled 3 time a day + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]

Outcomes

Primary Outcome Measures

Overall Survival

Secondary Outcome Measures

Hepatorenal syndrome
Score of Lille model
Percentage of Meld score (Model for End-stage Liver Disease) higher than 17

Full Information

First Posted
October 1, 2010
Last Updated
May 31, 2011
Sponsor
University Hospital, Lille
Collaborators
Ministry of Health, France
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1. Study Identification

Unique Protocol Identification Number
NCT01214226
Brief Title
Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis
Acronym
CorpentoxHAA
Official Title
Evaluation of the Survival Benefit of the Adjunction of Pentoxifylline to Corticosteroids in Patients Suffering From Severe Alcoholic Hepatitis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2010
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
January 2011 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
University Hospital, Lille
Collaborators
Ministry of Health, France

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis, Alcoholic Liver Disease

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Pentoxifylline + Prednisolone
Arm Type
Active Comparator
Arm Description
Pentoxifylline 400 mg prolonged-released tablets 3 time a day [1200 mg/day] + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]
Arm Title
Placebo + Prednisolone
Arm Type
Placebo Comparator
Arm Description
Placebo prolonged-release tabled 3 time a day + Prednisolone 2 ORODISPERSIBLE TABLETS OF 20 MG 1 TIME PER DAY [40 mg/day]
Intervention Type
Drug
Intervention Name(s)
Pentoxifylline
Other Intervention Name(s)
TORENTAL 400MG
Intervention Description
400 mg prolonged-released tablets 3 time per day for 1 month.
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
prolonged-release tablets 3 time per day for 1 month
Primary Outcome Measure Information:
Title
Overall Survival
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Hepatorenal syndrome
Time Frame
6 months
Title
Score of Lille model
Time Frame
Seven days
Title
Percentage of Meld score (Model for End-stage Liver Disease) higher than 17
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Philippe MATHURIN, MD PhD
Organizational Affiliation
University Hospital, Lille
Official's Role
Principal Investigator
Facility Information:
Facility Name
University hospital
City
Brussel
ZIP/Postal Code
1070
Country
Belgium
Facility Name
University hospital
City
Angers
ZIP/Postal Code
49933
Country
France
Facility Name
Hôpital Jean Verdier (AH-HP)
City
Bondy
ZIP/Postal Code
93143
Country
France
Facility Name
University hospital
City
Bordeaux
ZIP/Postal Code
33000
Country
France
Facility Name
Centre hospitalier
City
Béthune
ZIP/Postal Code
62408
Country
France
Facility Name
University hospital
City
Caen
ZIP/Postal Code
14000
Country
France
Facility Name
Hospital Antoine Béclère (Assistance Publique des Hôpiaux de Paris)
City
Clamart
ZIP/Postal Code
92141
Country
France
Facility Name
Hôpital Beaujon (AH-HP)
City
Clichy
ZIP/Postal Code
92118
Country
France
Facility Name
Centre Hospitalier
City
Creil
ZIP/Postal Code
60100
Country
France
Facility Name
Hôpital Henri Mondor (AP-HP)
City
Créteil
ZIP/Postal Code
94000
Country
France
Facility Name
Centre hospitalier
City
Dunkerque
ZIP/Postal Code
59240
Country
France
Facility Name
Centre Hospitalier
City
Lens
ZIP/Postal Code
62300
Country
France
Facility Name
University hospital
City
Lille
ZIP/Postal Code
59037
Country
France
Facility Name
Centre hospitalier Sambre en avesnois
City
Maubeuge
ZIP/Postal Code
59600
Country
France
Facility Name
University hospital
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
University hospital
City
Nantes
ZIP/Postal Code
45000
Country
France
Facility Name
University hospital
City
Nice
ZIP/Postal Code
06202
Country
France
Facility Name
Hôpital Saint Antoine (AP-HP)
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Hôpital de la Pitié-Salpétrière (AP-HP)
City
Paris
ZIP/Postal Code
75013
Country
France
Facility Name
Hôpital Cochin (AH-HP)
City
Paris
ZIP/Postal Code
75014
Country
France
Facility Name
University hospital
City
Poitiers
ZIP/Postal Code
49000
Country
France
Facility Name
University hospital
City
Rennes
ZIP/Postal Code
35033
Country
France
Facility Name
Centre Hospitalier Victor Provo
City
Roubaix
ZIP/Postal Code
59100
Country
France
Facility Name
University Hospital
City
Strasbourg
ZIP/Postal Code
67100
Country
France
Facility Name
Centre Hospitalier
City
Tourcoing
ZIP/Postal Code
59208
Country
France
Facility Name
Centre Hospitalier
City
Valenciennes
ZIP/Postal Code
59300
Country
France
Facility Name
University hospital, Nancy
City
Vandoeuvre les nancy
ZIP/Postal Code
54511
Country
France
Facility Name
Hôpital Paul Brousse (AH-HP)
City
Villejuif
ZIP/Postal Code
94000
Country
France

12. IPD Sharing Statement

Citations:
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
result
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
result
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
result
PubMed Identifier
16026887
Citation
Mathurin P. Corticosteroids for alcoholic hepatitis--what's next? J Hepatol. 2005 Sep;43(3):526-33. doi: 10.1016/j.jhep.2005.06.003. No abstract available.
Results Reference
result
PubMed Identifier
15122768
Citation
Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D; Foie-Alcool group of the Association Francaise pour l'Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology. 2004 May;39(5):1390-7. doi: 10.1002/hep.20206.
Results Reference
result
PubMed Identifier
14647046
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;38(6):1363-9. doi: 10.1016/j.hep.2003.09.038.
Results Reference
result
PubMed Identifier
11943418
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 three randomized placebo controlled double blind trials of corticosteroids in severe AH. J Hepatol. 2002 Apr;36(4):480-7. doi: 10.1016/s0168-8278(01)00289-6.
Results Reference
result
PubMed Identifier
8964410
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):1847-53. doi: 10.1053/gast.1996.v110.pm8964410.
Results Reference
result
PubMed Identifier
1531090
Citation
Ramond MJ, Poynard T, Rueff B, Mathurin P, Theodore 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. doi: 10.1056/NEJM199202203260802.
Results Reference
result
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
derived

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Double-blind Randomized Controlled Trial in Severe Alcoholic Hepatitis

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