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Corticosteroids in Alcoholic Hepatitis

Primary Purpose

Alcoholic Hepatitis

Status
Unknown status
Phase
Not Applicable
Locations
Belgium
Study Type
Interventional
Intervention
Methylprednisolone or placebo
Sponsored by
Erasme University Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alcoholic Hepatitis focused on measuring alcoholic hepatitis, spontaneous improvement, corticosteroids

Eligibility Criteria

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

Inclusion Criteria:

  1. Clinical syndrome of alcoholic hepatitis:

    recent jaudice or in recent aggravation (< 3 months) serum bilirubin > 5 mg/dL history of excess alcohol abuse (> 40g/day)

  2. Alcoholic hepatitis proven by a liver biopsy (histological criteria of alcoholic hepatitis defined according to EASL clinical practice guidelines : steatosis, hepatocyte ballooning, and an inflammatory infiltrate with PMNs). The results of the liver biopsy are not mandatory for inclusion. However, the biopsy must be planned at the latest on day 1. When the results become available and do not confirm alcoholic hepatitis, the patient must discontinue the study.
  3. Spontaneous liver function improvement, defined by a decrease in serum bilirubin level > 10% between admission and day 5-10 after admission
  4. less than 2 weeks since admission to hospital
  5. Maddrey discriminant function* greater than or equal to 32
  6. Subjects must voluntarily sign and date an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures.
  7. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements.

Patients with significant hepatic encephalopathy are not excluded from participation to the trial. In this case, the patient should be accompanied by a legal representative that will decide participation in the clinical study and sign ICF.

Exclusion Criteria:

  1. Other causes of liver disease including viral hepatitis (positive HBs antigen, HCV RNA positive), auto-immune hepatitis, biliary obstruction
  2. Other disease compromising 90-day survival
  3. Positive HIV serology
  4. Uncontrolled infection All patients will be screened for infection. This will involve chest radiography, urinalysis, PMNs count in ascites (if ascites present). All other sign or clinical suspicion of infection with or without antibiotherapy will be recorded as an infection.

    Positive culture and initiation of antibiotics with clinical or radiological signs of infection, as well as clinical suspicion, will be recorded as infection.

    Patients with evidence of sepsis will be treated for a minimum of 2 days with appropriate antibiotics. Once the local principal investigator considers that the sepsis is under control, the patient may be rescreened and randomised.

  5. Uncontrolled gastrointestinal bleeding Bleeding must be judged as controlled for at least 5 days
  6. Patient with serum creatinine > 2.5 mg/dL, under renal replacement therapy or under terlipressine (or other vasoactive drugs)
  7. Pentoxyphilline therapy
  8. Pregnant or lactating women

Sites / Locations

  • CUB Hôpital ErasmeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

methylprednisolone

placebo

Arm Description

Patients will receive 28 days of methylprednisolone 32 mg/day

Patients will receive 28 days of matching placebo

Outcomes

Primary Outcome Measures

Mortality at 90 days
To determine whether Methylprednisolone compared to placebo improve the 90 day mortality from patients with severe AH and spontaneous improvement of liver function

Secondary Outcome Measures

Mortality at 28 days
To determine the 28 day mortality from patients with severe AH and spontaneous liver function improvement treated with Methylprednisolone or placebo
Incidence of infections during the study period (90 days)
To determine the incidence of infections during the 90 day study period in corticosteroid-treated compared to placebo-treated patients

Full Information

First Posted
May 18, 2017
Last Updated
February 24, 2021
Sponsor
Erasme University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03160651
Brief Title
Corticosteroids in Alcoholic Hepatitis
Official Title
Corticosteroids in Severe Alcoholic Hepatitis Patients With Early Spontaneous Improvement
Study Type
Interventional

2. Study Status

Record Verification Date
February 2021
Overall Recruitment Status
Unknown status
Study Start Date
February 9, 2018 (Actual)
Primary Completion Date
June 2022 (Anticipated)
Study Completion Date
December 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Erasme University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Approximately 50% of patients admitted for severe AH will have spontaneous improvement of liver function before initiation of therapy (ie decrease in mDF between hospital admission and initiation of steroids). These patients have a better prognosis than patients without spontaneous improvement of liver function. It has never been demonstrated that corticosteroids improve survival in severe AH patients with spontaneous improvement of liver function. Our hypothesis is that severe AH patients with spontaneous improvement of liver function represent a group who could most benefit from steroids

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alcoholic Hepatitis
Keywords
alcoholic hepatitis, spontaneous improvement, corticosteroids

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
double-blind randomized trial Investigator, patients, and care providers will be masking Only statisticians and pharmacist will not be masking
Allocation
Randomized
Enrollment
140 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
methylprednisolone
Arm Type
Active Comparator
Arm Description
Patients will receive 28 days of methylprednisolone 32 mg/day
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
Patients will receive 28 days of matching placebo
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone or placebo
Intervention Description
Patients will receive 28 days of methylprednisolone 32 mg/day
Primary Outcome Measure Information:
Title
Mortality at 90 days
Description
To determine whether Methylprednisolone compared to placebo improve the 90 day mortality from patients with severe AH and spontaneous improvement of liver function
Time Frame
90 days
Secondary Outcome Measure Information:
Title
Mortality at 28 days
Description
To determine the 28 day mortality from patients with severe AH and spontaneous liver function improvement treated with Methylprednisolone or placebo
Time Frame
28 days
Title
Incidence of infections during the study period (90 days)
Description
To determine the incidence of infections during the 90 day study period in corticosteroid-treated compared to placebo-treated patients
Time Frame
90 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Clinical syndrome of alcoholic hepatitis: recent jaudice or in recent aggravation (< 3 months) serum bilirubin > 5 mg/dL history of excess alcohol abuse (> 40g/day) Alcoholic hepatitis proven by a liver biopsy (histological criteria of alcoholic hepatitis defined according to EASL clinical practice guidelines : steatosis, hepatocyte ballooning, and an inflammatory infiltrate with PMNs). The results of the liver biopsy are not mandatory for inclusion. However, the biopsy must be planned at the latest on day 1. When the results become available and do not confirm alcoholic hepatitis, the patient must discontinue the study. Spontaneous liver function improvement, defined by a decrease in serum bilirubin level > 10% between admission and day 5-10 after admission less than 2 weeks since admission to hospital Maddrey discriminant function* greater than or equal to 32 Subjects must voluntarily sign and date an informed consent form, approved by an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) prior to the initiation of any screening or study-specific procedures. Subjects must be able to understand and adhere to the study visit schedule and all other protocol requirements. Patients with significant hepatic encephalopathy are not excluded from participation to the trial. In this case, the patient should be accompanied by a legal representative that will decide participation in the clinical study and sign ICF. Exclusion Criteria: Other causes of liver disease including viral hepatitis (positive HBs antigen, HCV RNA positive), auto-immune hepatitis, biliary obstruction Other disease compromising 90-day survival Positive HIV serology Uncontrolled infection All patients will be screened for infection. This will involve chest radiography, urinalysis, PMNs count in ascites (if ascites present). All other sign or clinical suspicion of infection with or without antibiotherapy will be recorded as an infection. Positive culture and initiation of antibiotics with clinical or radiological signs of infection, as well as clinical suspicion, will be recorded as infection. Patients with evidence of sepsis will be treated for a minimum of 2 days with appropriate antibiotics. Once the local principal investigator considers that the sepsis is under control, the patient may be rescreened and randomised. Uncontrolled gastrointestinal bleeding Bleeding must be judged as controlled for at least 5 days Patient with serum creatinine > 2.5 mg/dL, under renal replacement therapy or under terlipressine (or other vasoactive drugs) Pentoxyphilline therapy Pregnant or lactating women
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Christophe Moreno, MD, PhD
Phone
+32 2 5553714
Email
christophe.moreno@erasme.ulb.ac.be
First Name & Middle Initial & Last Name or Official Title & Degree
Françoise Smits, Nurse
Phone
+32 2 5554478
Email
francoise.smits@erasme.ulb.ac.be
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christophe Moreno, MD, PhD
Organizational Affiliation
Erasme University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
CUB Hôpital Erasme
City
Brussels
ZIP/Postal Code
1070
Country
Belgium
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christophe Moreno, MD
Email
christophe.moreno@erasme.ulb.ac.be

12. IPD Sharing Statement

Plan to Share IPD
No
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
background
PubMed Identifier
352788
Citation
Maddrey WC, Boitnott JK, Bedine MS, Weber FL Jr, Mezey E, White RI Jr. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978 Aug;75(2):193-9.
Results Reference
background
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
background
PubMed Identifier
2648927
Citation
Carithers RL Jr, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial. Ann Intern Med. 1989 May 1;110(9):685-90. doi: 10.7326/0003-4819-110-9-685.
Results Reference
background
PubMed Identifier
22633836
Citation
European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012 Aug;57(2):399-420. doi: 10.1016/j.jhep.2012.04.004. Epub 2012 May 26. No abstract available.
Results Reference
background
PubMed Identifier
20034030
Citation
O'Shea RS, Dasarathy S, McCullough AJ; Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology. 2010 Jan;51(1):307-28. doi: 10.1002/hep.23258. No abstract available.
Results Reference
background
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
25901427
Citation
Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S, Masson S, McCune A, Mellor J, O'Grady J, Patch D, Ratcliffe I, Roderick P, Stanton L, Vergis N, Wright M, Ryder S, Forrest EH; STOPAH Trial. Prednisolone or pentoxifylline for alcoholic hepatitis. N Engl J Med. 2015 Apr 23;372(17):1619-28. doi: 10.1056/NEJMoa1412278.
Results Reference
background

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Corticosteroids in Alcoholic Hepatitis

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