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The Effect of Gut Sterilisation on Macrophage Activation in Patients With Alcoholic Hepatitis.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03157388
Recruitment Status : Completed
First Posted : May 17, 2017
Last Update Posted : May 23, 2019
Information provided by (Responsible Party):
University of Aarhus

Brief Summary:

Alcoholic hepatitis (AH) is a severe alcohol induced hepatic inflammation that leads to jaundice and liver failure. Gut derived bacterial translocation to the liver is currently thought to be one of the main inflammatory drivers of the disease.

This project investigates the effects of gut sterilisation with broad spectrum antibiotics in patients with AH

Condition or disease Intervention/treatment Phase
Alcoholic Hepatitis Drug: Combined Vancomycin and Gentamycin and Meropenem Not Applicable

Detailed Description:

Alcoholic hepatitis (AH) is a severe alcohol induced hepatic inflammation that leads to jaundice and liver failure. The incidence of AH is increasing and the disease is associated with a high mortality. In spite of numerous clinical trials both treatment and prognosis have remained essentially unchanged for decades, emphasizing the need to improve our understanding of the disease mechanisms behind AH.

The current perception of the pathogenesis of alcohol-induced liver injury mainly derives from animal models, and the resident hepatic macrophages, the Kupffer cells, seem to play an important role. Activation of these cells may give rise to most of the hallmark clinical findings of AH: The cytokines released initiate hepatic inflammation and an acute phase response, recruit neutrophils, and activate stellate cells, contributing to the acute portal hypertension. Jaundice is due to intrahepatic cholestasis caused by down regulation of the bilirubin transporters on the basolateral hepatocyte membrane. Hepatic macrophages are thought to be activated by the bacterial derived endotoxins/lipopolysaccharides (LPS) present in the portal blood because of an alcohol-induced increase in gut-blood permeability with translocation of bacteria, as found in patients with alcoholic liver injury. LPS is recognized by the hepatic macrophages via a membrane complex including the pathogen recognition receptor molecule Toll-like receptor 4 (TLR-4). LPS Binding Proteins (LBP) produced by hepatocytes then bind and present LPS to the membrane glycoprotein CD14 that in turn activates TLR-4. In support of these mechanisms, alcohol-induced liver injury is reduced in knockout mice missing LBP, CD14, and TLR-4. Likewise, chemical destruction of hepatic macrophages in rats prevents alcohol-induced liver injury, as does cleansing the gut flora with antibiotics.

Human hepatic macrophages when activated, express their surface receptor CD163. We and others have previously shown that sCD163 is released from the liver in alcoholic liver disease, that its plasma concentration predicts mortality in patients with acute liver failure and is as a marker of portal hypertension and a predictor of clinical decompensation in patients with liver cirrhosis. Very recently we have directly demonstrated hepatic macrophage activation in human AH paralleling the disease severity, and to suggest this to be elicited by LPS.

The line of evidence presented above provides rationale for testing whether intervention toward bacterial translocation may result in a diminished immune response in human AH. Consequently, in this study the investigators seek to perform total gut microbiota eradication by combining 3 different orally administered antibiotics. The investigators have chosen antibiotics that are not absorbed into the systemic circulation, because the investigators want to limit the effects to the gastrointestinal tract.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 15 patients with alcoholic hepatitis will be consecutively included and compared to a historical cohort of AH patients
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: The Effect of Gut Sterilisation on Macrophage Activation in Patients With Alcoholic Hepatitis.
Actual Study Start Date : June 1, 2017
Actual Primary Completion Date : June 1, 2018
Actual Study Completion Date : December 1, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Intervention
Combined Vancomycin and Gentamycin and Meropenem
Drug: Combined Vancomycin and Gentamycin and Meropenem

The following combined antibiotic regime will be administered for eradication of gut bacteria.

7 days combined antibiotic treatment, per oral route, once daily: vancomycin 500 mg (Vancomycin "Hospira"), powder for concentrate and gentamycin 40 mg ("Hexamycin®"), solution and meropenem 500 mg (Meropenem "Hospira"), powder for concentrate; The three drugs are dissolved and combined in approximately 100 ml of apple juice.

Primary Outcome Measures :
  1. Macrophage activation cd163 [ Time Frame: 1 year ]
    Difference in serum levels of macrophage activation markers sCD163

Secondary Outcome Measures :
  1. LBP [ Time Frame: 1 year ]
    serum levels of Lipopolysaccaride binding protein

  2. TNF alfa [ Time Frame: 1 year ]
    serum levels of, Tumor Necrosis Factor-alfa

  3. Interleukin-1b [ Time Frame: 1 year ]
    serum levels of, Interleukin-1b

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

A first time diagnose of AH by a combination of physical and laboratory criteria:

  1. A history of excessive alcohol ingestion (10 units or more per day) until at least three weeks before admission
  2. Acute jaundice (developed over at most 2 weeks, serum bilirubin > 80 μmol/l).
  3. liverbiopsy will be performed in case of doubt regarding the diagnosis.

Exclusion Criteria:

  1. Non-native speaking Danish
  2. Viral hepatitis,
  3. Autoimmune liver disease,
  4. Bile duct obstruction,
  5. Liver tumours or any other cancer,
  6. Presence of an infectious focus (either clinically assessed or based on chest x-ray, urine samples or ascites puncture),
  7. On-going gastrointestinal bleeding or bleeding within the previous three months
  8. Any prior immune-modulating therapy.
  9. Any known gastrointestinal disease
  10. Contraindications against/allergy towards the used antibiotics

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 identifier (NCT number): NCT03157388

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Aarhus University Hospital
Aarhus, Denmark, 8000
Sponsors and Collaborators
University of Aarhus
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Study Director: Hendrik D Vilstrup, Professor Aarhus University Hospital
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Responsible Party: University of Aarhus Identifier: NCT03157388    
Other Study ID Numbers: 1-10-72-1-15
First Posted: May 17, 2017    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Aarhus:
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis, Alcoholic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Liver Diseases, Alcoholic
Alcohol-Induced Disorders
Alcohol-Related Disorders
Substance-Related Disorders
Chemically-Induced Disorders
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action