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

May 22, 2019 updated by: University of Aarhus

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
15

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Aarhus, Denmark, 8000
        • Aarhus University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 75 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Macrophage activation cd163
Time Frame: 1 year
Difference in serum levels of macrophage activation markers sCD163
1 year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
LBP
Time Frame: 1 year
serum levels of Lipopolysaccaride binding protein
1 year
TNF alfa
Time Frame: 1 year
serum levels of, Tumor Necrosis Factor-alfa
1 year
Interleukin-1b
Time Frame: 1 year
serum levels of, Interleukin-1b
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Aarhus

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Hendrik D Vilstrup, Professor, Aarhus University Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2017

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2018

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 15, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 16, 2017

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 17, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 23, 2019

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 22, 2019

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 1-10-72-1-15

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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