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Liver CirrhosisPhase 4NCT06630572

Rifaximin in Cirrhosis: Effects on Endotoxin and Haemostatic Indexes

A Phase 4 study testing Rifaximin in people with Liver Cirrhosis and Coagulation Disorder, run by University of Roma La Sapienza at 1 site in Italy.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 75 years
What is being tested?
Rifaximin
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
20 participants
Where
1 siteItaly
Study dates
3 Apr 2021to 1 Aug 2024
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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
Show all 13Show fewer
  • 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.

Trial locations and contacts

1 site in 1 country.

Italy1 site
  • Sapienza University of Rome - Policlinico Umberto I Roma

    Rome, 00161

Other trials in Italy

About this study

Official title: 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.

Read the 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.

Being tested
Rifaximin, Placebo
Keywords
Rifaximin, Liver Cirrhosis, Endotoxin, Platelet function
Medical subject headings
Liver Cirrhosis, Hemostatic Disorders, Blood Platelet Disorders, Endotoxemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RifaximinDrug

    Patients randomized to receive Rifaximin for 14 days

  • PlaceboDrug

    Patients randomized to receive Placebo for 14 days

Study groups in NCT06630572
Study groupRoleWhat they receive
TREATMENTExperimentalRifaximin (1100 mg/die) - 550 b.i.d.
Receives: Drug: Rifaximin
PLACEBOPlacebo comparatorPlacebo - b.i.d.
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Decrease in serum endotoxemia after 14-day treatment with Rifaximin.

    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.

    Measured: 14, 30, 60 Days

Secondary outcomes (3)
  1. Impact of serum changes of LPS on coagulation and/or platelet indexes

    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.

    Measured: 14, 30, 60 Days

  2. Clinical Failure

    Proportion of patients with clinical failure.

    Measured: 14, 30, 60 Days

  3. Safety and tolerability: Number of participants with adverse events as a measure of safety and tolerability

    Number of participants with adverse events as a measure of safety and tolerability

    Measured: 14, 30, 60 Days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Oct 2024
  2. Study start3 Apr 2021
  3. Primary completion3 Apr 2022
  4. Study completion1 Aug 2024

Why it stopped: Because drug is expired

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Randomized, placebo control, double-blind trial.
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06630572
Sponsor's protocol ID
EudraCT 2017-000488-34
Status last verified
Aug 2024
First submitted
18 Jan 2018
Last updated
8 Oct 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Violi F, Ferro D. Clotting activation and hyperfibrinolysis in cirrhosis: implication for bleeding and thrombosis. Semin Thromb Hemost. 2013 Jun;39(4):426-33. doi: 10.1055/s-0033-1334144. Epub 2013 Mar 13.

    PubMed 23487343
  • Violi F, Ferro D, Basili S, Lionetti R, Rossi E, Merli M, Riggio O, Bezzi M, Capocaccia L. Ongoing prothrombotic state in the portal circulation of cirrhotic patients. Thromb Haemost. 1997 Jan;77(1):44-7.

    PubMed 9031447
  • Nolan JP. The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology. 2010 Nov;52(5):1829-35. doi: 10.1002/hep.23917.

    PubMed 20890945
  • Raparelli V, Basili S, Carnevale R, Napoleone L, Del Ben M, Nocella C, Bartimoccia S, Lucidi C, Talerico G, Riggio O, Violi F. Low-grade endotoxemia and platelet activation in cirrhosis. Hepatology. 2017 Feb;65(2):571-581. doi: 10.1002/hep.28853. Epub 2016 Nov 5.

    PubMed 27641757
  • Violi F, Basili S, Raparelli V, Chowdary P, Gatt A, Burroughs AK. Patients with liver cirrhosis suffer from primary haemostatic defects? Fact or fiction? J Hepatol. 2011 Dec;55(6):1415-27. doi: 10.1016/j.jhep.2011.06.008. Epub 2011 Jun 28.

    PubMed 21718668
  • Ferro D, Angelico F, Caldwell SH, Violi F. Bleeding and thrombosis in cirrhotic patients: what really matters? Dig Liver Dis. 2012 Apr;44(4):275-9. doi: 10.1016/j.dld.2011.10.016. Epub 2011 Nov 25.

    PubMed 22119620
  • Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP. Rifaximin treatment in hepatic encephalopathy. N Engl J Med. 2010 Mar 25;362(12):1071-81. doi: 10.1056/NEJMoa0907893.

    PubMed 20335583
  • Rivkin A, Gim S. Rifaximin: new therapeutic indication and future directions. Clin Ther. 2011 Jul;33(7):812-27. doi: 10.1016/j.clinthera.2011.06.007. Epub 2011 Jul 7.

    PubMed 21741091
  • Danulescu RM, Ciobica A, Stanciu C, Trifan A. The role of rifaximine in the prevention of the spontaneous bacterial peritonitis. Rev Med Chir Soc Med Nat Iasi. 2013 Apr-Jun;117(2):315-20.

    PubMed 24340510

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Rifaximin in people with Liver Cirrhosis and Coagulation Disorder, run by University of Roma La Sapienza at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Because drug is expired). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Decrease in serum endotoxemia after 14-day treatment with Rifaximin. (time frame: 14, 30, 60 Days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06630572, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Oct 2024.

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