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Randomised Open-label Multicenter Study Evaluating Ciprofloxacin in Severe Alcoholic Hepatitis

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ClinicalTrials.gov Identifier: NCT02326103
Recruitment Status : Completed
First Posted : December 25, 2014
Last Update Posted : January 19, 2017
Sponsor:
Information provided by (Responsible Party):
Markku Nissinen, Helsinki University

Brief Summary:
The study is aimed to evaluate the additional role of ciprofloxacin therapy in severe alcoholic hepatitis combined to prednisolone therapy in an open-label placebo controlled manner.

Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Alcoholic Cirrhosis Drug: Ciprofloxacin Drug: Placebo Early Phase 1

Detailed Description:

Introduction: Alcoholic hepatitis (AH) is an inflammatory liver injury associated with longstanding excess alcohol consumption. Disease spectrum varies from asymptomatic transaminase elevations to fulminate liver failure. In hospital mortality in patients with severe alcoholic hepatitis not responding to corticosteroids is over 30 %.

Alcohol increases gut permeability and promotes the translocation of lipopolysaccharide (LPS) from the gut lumen the portal vein, and further to Kupffer cells, where LPS binds to CD14, ultimately activating multiple cytokine genes.

Diagnosis of AH is based on history of heavy alcohol use, symptoms like jaundice and on typical laboratory findings, and in uncertain cases on liver biopsy.

Determination of the severity of alcoholic hepatitis is essential for assessment of the disease prognosis and selection therapy. Cessation of alcohol consumption is mandatory for further therapy. Several scoring systems are available to assess the severity and the prognosis of alcohol hepatitis. Maddrey discrimination function (DF) is most widely used and enables to identify patients with severe alcohol hepatitis responding to corticosteroid therapy.

The first line therapy in severe alcoholic hepatitis (DF≥32) is prednisolone. However, those not responding to steroids have 77 % 6 months mortality.

New treatment options for severe AH are desperately needed. Although increased bacterial and LPS translocation are considered to have central role in the pathogenesis of AH no controlled studies of antibiotics in alcoholic hepatitis has been published. In Finland 600 AH requiring hospitalization are diagnosed annually.

Study objective: To evaluate to additional role of ciprofloxacin therapy in severe alcoholic hepatitis combined to prednisolone therapy.

Moreover, we try to find new and better predictors for liver injury and treatment response.

Patients: 150 AH patients, with Maddrey DF >32.

Randomization: Patients with severe AH are randomized at hospitalization 1:1 to receive:

  1. Prednisolone 40 mg/day for 1 month, with decreasing by 5 mg/week + ciprofloxacin 1000 mg/ day for 120 days or
  2. Prednisolone 40 mg/day for 1 month, with decreasing by 5 mg/week + placebo/ day for 120 days Measurement of response Early change in bilirubin levels (ECBL= S-Bil(Day 0)-S-Bil(Day7 )>0 Lille Score >0.45 day 7. Change in serum sterol levels as surrogate markers of cholesterol synthesis (reflecting liver function and severity of cholestasis) Primary end point Mortality at day 28, at 6 months and at 12 months Secondary end points: Proportion of patients with early change in bilirubin levels (ECBL= S-Bil(Day 0)-S-Bil(Day7 )>0 Proportion of patients with Lille Score >0.45 day 7 Recovery of liver function parameters in 1 and 3 months

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomised Open-label Multicenter Study Evaluating Ciprofloxacin in Severe Alcoholic Hepatitis in Addition to Prednisolon Therapy
Study Start Date : April 2015
Actual Primary Completion Date : January 2017
Actual Study Completion Date : January 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Ciprofloxacin
Oral administration of Ciprofloxacin 500mg twice daily
Drug: Ciprofloxacin
Comparison of ciprofloxacin with placebo in alcoholic hepatitis

Placebo Comparator: Placebo
Oral administration of Placebo pill twice daily
Drug: Placebo



Primary Outcome Measures :
  1. Death at 28 days [ Time Frame: 28 days after randomisation ]
  2. Death at 3 months [ Time Frame: 3 months after randomisation ]
  3. Death at 6 months [ Time Frame: 6 months after randomisation ]

Secondary Outcome Measures :
  1. Early reduction in serum bilirubin level [ Time Frame: 7 days after randomisation ]
  2. Surrogate markers of liver function [ Time Frame: 7 days to 12 months ]
    Improvement of surrogate markers of cholesterol synthesis and liver synthesis capacity, e.g., lathosterol, cholestenol and desmosterol



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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Severe alcoholic hepatitis; Maddrey above 300

Exclusion Criteria:

Viral hepatitis Remarkable bleeding in the gastrointestinal tract Serious bacterial infection Hepatorenal syndrome Earlier participation in this study Malignant disease not in remission Other liver disease affecting remarkably the outcome of alcoholic liver disease Mental retardation


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): NCT02326103


Locations
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Finland
University Hospital of Helsinki
Helsinki, Finland, 00029HUS
Sponsors and Collaborators
Helsinki University
Investigators
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Principal Investigator: Perttu Sahlman, MD University Hospital of Helsinki

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Responsible Party: Markku Nissinen, chief specialist, Helsinki University
ClinicalTrials.gov Identifier: NCT02326103     History of Changes
Other Study ID Numbers: HELSINKIU
First Posted: December 25, 2014    Key Record Dates
Last Update Posted: January 19, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No IPD will be shared with other researchers during the study or during the analysis of the results.

Keywords provided by Markku Nissinen, Helsinki University:
alcoholic
hepatitis
cirrhosis
cholesterol metabolites
ciprofloxacin

Additional relevant MeSH terms:
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Liver Cirrhosis, Alcoholic
Liver Diseases
Liver Diseases, Alcoholic
Liver Cirrhosis
Hepatitis
Hepatitis A
Fibrosis
Hepatitis, Alcoholic
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Pathologic Processes
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Ciprofloxacin
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors