Clinical trial NCT06630572: Rifaximin in Cirrhosis: Effects on Endotoxin and Haemostatic Indexes
Official title: Rifaximin Blunted Higher Levels of Endotoxin in Cirrhosis Patients: a Randomized, Double Blind, Short Term Interventional Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Liver Cirrhosis
Coagulation Disorder
Platelet Disorder
Endotoxemia
Keywords: Rifaximin
Liver Cirrhosis
Endotoxin
Platelet function
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
Collaborators: name: Azienda Policlinico Umberto I
First posted: 2024-10-08
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, placebo control, double-blind trial.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Decrease in serum endotoxemia after 14-day treatment with Rifaximin.
timeFrame: 14, 30, 60 Days
Secondary outcomes:
measure: Impact of serum changes of LPS on coagulation and/or platelet indexes
timeFrame: 14, 30, 60 Days
measure: Clinical Failure
timeFrame: 14, 30, 60 Days
measure: Safety and tolerability: Number of participants with adverse events as a measure of safety and tolerability
timeFrame: 14, 30, 60 Days
Other outcomes:
measure: Platelet activation
timeFrame: 14, 30, 60 Days
measure: Platelet- leukocyte aggregation
timeFrame: 14, 30, 60 Days
measure: Platelet turnover
timeFrame: 14, 30, 60 Days
measure: Gut microbiota
timeFrame: 14, 30, 60 Days
measure: Neutrophil extracellular traps (NETs)
timeFrame: 14, 30, 60 Days
measure: Gut microbiota
timeFrame: 14, 30, 60 Days
Locations:
city: Rome
country: Italy
facility: Sapienza University of Rome - Policlinico Umberto I Roma
Study officials:
affiliation: SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
name: Stefania BASILI, Prof.
role: STUDY_CHAIR
affiliation: SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
name: Oliviero Riggio, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
name: Manuela Merli, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: SAPIENZA UNIVERSITY- Department of Translational and Precision Medicine
name: Lucia Stefanini, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: SAPIENZA UNIVERSITY
name: Roberto Carnevale, Prof.
role: PRINCIPAL_INVESTIGATOR
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