Rifaximin in Cirrhosis: Effects on Endotoxin and Haemostatic Indexes

October 3, 2024 updated by: Stefania Basili, University of Roma La Sapienza

Rifaximin Blunted Higher Levels of Endotoxin in Cirrhosis Patients: a Randomized, Double Blind, Short Term Interventional Trial

Rifaximin is an antibiotic that acts locally in the gastrointestinal tract with a broad spectrum of antibacterial activity. The efficacy of rifaximin is well documented in the prevention of acute hepatic encephalopathy. There is no evidence on its benefit to modulate hypercoagulative state in cirrhotic patient.

To assess the effect of a short-term treatment with rifaximin on systemic levels of intestinal endotoxin and on platelet and coagulation markers in patients with decompensated cirrhosis the study has been planned.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

The term coagulopathy has been coined because of impaired clotting activation detected by laboratory tests in association with deterioration of liver function; the frequent coexistence of hyperfibrinolysis, low platelet count, and platelet dysfunction reinforced the concept that coagulopathy is associated with cirrhosis.

This concept has been recently challenged for several reasons. The prolongation of global tests of clotting activation does not actually reflect hemostatic changes in vivo and maybe a laboratory artefact. In addition, cirrhotic patients actually disclose a tendency to a hypercoagulation state, which seems to be related to endotoxemia and may be detected in both peripheral and portal circulation, and to an increased platelet activation.

Bacterial lipopolysaccharide (LPS, endotoxin) is elevated in cirrhosis, particularly in decompensated cirrhosis, with a mechanism related to an enhanced gut permeability and ensuing translocation of LPS in the peripheral circulation. Recent data demonstrated that cirrhosis is associated with a low-grade endotoxemia, which is more evident in Child-Pugh classes B and C. Of note, LPS significantly correlated with sCD40L and sPs, suggesting a role for LPS in eliciting platelet activation.

It is difficult to believe that under these circumstances patients with cirrhosis are at high risk of bleeding; thus, apart from gastrointestinal tract bleeding, which is independent of changes of the clotting system, spontaneous bleeding in cirrhosis is rare. Conversely, in vivo data reporting the existence of platelet and clotting activation may explain the increased risk for thrombosis overall in portal circulation. This opens a new and interesting scenario as portal vein thrombosis, which may occur in approximately 20% of cirrhotic patients, should be treated with antithrombotic drugs (https://clinicaltrials.gov/ct2/show/NCT01470547). However, planning trials with anticoagulants in cirrhosis will be very difficult because the persistent concept of "coagulopathy in cirrhosis" is likely to be a barrier against the use of anticoagulants.

Interventional trials to modulate low-grade endotoxemia are warranted to assess if this therapeutic approach may reduce the risk of thrombosis in cirrhosis.

In a small cohort of cirrhotic, a previous study demonstrated that administration of non-absorbable antibiotic reduces thrombin generation coincidentally with serum LPS reduction suggesting a role for LPS as trigger of clotting activation. No data were provided, however, on the effect of this treatment on platelet activation or on the duration of clotting system inhibition.

Rifaximin is an antibiotic that acts locally in the gastrointestinal tract with a broad spectrum of antibacterial activity. The efficacy of rifaximin is well documented in the prevention of acute hepatic encephalopathy (HE). It is recommended as a first-line therapy for HE and was recently approved for the prevention of HE in high-risk populations. More recently, clinical trials have been performed to evaluate the effect of this drug on the prophylaxis of spontaneous bacterial peritonitis (SBP) and other cirrhosis-related complications. Although these studies demonstrated excellent prospects for the clinical application of rifaximin, there is no evidence on its benefit to modulate hypercoagulative state in the cirrhotic patient.

Study objective: to assess the effect of a short-term (14 days) treatment with rifaximin (1100 mg/die) on systemic levels of intestinal endotoxin and on platelet and coagulation markers in patients with decompensated cirrhosis.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 4

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

  • Italy
      • Rome, Italy, 00161
        • Sapienza University of Rome - Policlinico Umberto I Roma

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

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients aged 18-75 years
  • Patients of Child-Pugh grade B or C (decompensated liver cirrhosis, as confirmed by clinical symptoms and signs, laboratory results, ultrasound and spiral computed tomography)

Exclusion Criteria:

  • Presence of overt infection or sepsis
  • Treatment with systemic or non-absorbable antibiotic, aspirin or other non-steroidal anti-inflammatory drugs, antidepressant drugs in the previous 30 days
  • Recent need of transfusion of platelets or plasma
  • Presence of extra-hepatic malignancy
  • Active alcohol intake in the last 6 months
  • Pregnancy or breast feeding
  • Presence of overt HE, GI haemorrhage, SBP or other concurrent infections during the previous one month
  • Human immunodeficiency virus (HIV) infection
  • Chronic renal and/or respiratory insufficiency
  • Severe heart disease
  • Allergy to rifaximin
  • Active post-viral hepatitis requiring or on direct-acting antiviral (DAA) agents
  • Previous or active intestinal obstruction.

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: TREATMENT
Rifaximin (1100 mg/die) - 550 b.i.d.
Drug: Rifaximin
Patients randomized to receive Rifaximin for 14 days
Placebo Comparator: PLACEBO
Placebo - b.i.d.
Drug: Placebo
Patients randomized to receive Placebo for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Decrease in serum endotoxemia after 14-day treatment with Rifaximin.
Time Frame: 14, 30, 60 Days
Significant decrease (-20%) in serum bacterial LPS (endotoxemia) after 14-day treatment with Rifaximin 550 mg b.i.d respect to the control group as well as after 30 and 60 days from the end of the treatment.
14, 30, 60 Days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Impact of serum changes of LPS on coagulation and/or platelet indexes
Time Frame: 14, 30, 60 Days
Significant correlation between change in serum LPS and thrombin generation and/or platelet activation indexes in both groups to support the role of LPS as trigger of clotting activation and platelet activation.
14, 30, 60 Days
Clinical Failure
Time Frame: 14, 30, 60 Days
Proportion of patients with clinical failure.
14, 30, 60 Days
Safety and tolerability: Number of participants with adverse events as a measure of safety and tolerability
Time Frame: 14, 30, 60 Days
Number of participants with adverse events as a measure of safety and tolerability
14, 30, 60 Days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Platelet activation
Time Frame: 14, 30, 60 Days
Evaluation of soluble markers of platelet activation [Flow cytometric analysis and ELISA]
14, 30, 60 Days
Platelet- leukocyte aggregation
Time Frame: 14, 30, 60 Days
Evaluation of platelet-leukocyte aggregates by Flow cytometric analysis
14, 30, 60 Days
Platelet turnover
Time Frame: 14, 30, 60 Days
Determination of platelet indices indicative of elevated platelet turnover.
14, 30, 60 Days
Gut microbiota
Time Frame: 14, 30, 60 Days
Evaluation of intestinal barrier permeability, by ELISA for LPS, marker of gut permeability.
14, 30, 60 Days
Neutrophil extracellular traps (NETs)
Time Frame: 14, 30, 60 Days
Soluble markers of neutrophil extracellular trap (NET) in circulation.
14, 30, 60 Days
Gut microbiota
Time Frame: 14, 30, 60 Days
Evaluation of intestinal barrier permeability, by ELISA for Zonulin, marker of gut permeability.
14, 30, 60 Days

Collaborators and Investigators

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

Sponsor

University of Roma La Sapienza

Collaborators

Azienda Policlinico Umberto I

Investigators

  • Study Chair: Stefania BASILI, Prof., SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
  • Principal Investigator: Oliviero Riggio, Prof., SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
  • Principal Investigator: Manuela Merli, Prof., SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
  • Principal Investigator: Lucia Stefanini, Prof., SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
  • Principal Investigator: Roberto Carnevale, Prof., Sapienza University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

April 3, 2021

Primary Completion (Actual)

April 3, 2022

Study Completion (Actual)

August 1, 2024

Study Registration Dates

First Submitted

January 18, 2018

First Submitted That Met QC Criteria

October 3, 2024

First Posted (Actual)

October 8, 2024

Study Record Updates

Last Update Posted (Actual)

October 8, 2024

Last Update Submitted That Met QC Criteria

October 3, 2024

Last Verified

August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT 2017-000488-34

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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