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Randomised Controlled Trial of Mechanistic Effects of Rifaximin in Cirrhosis and Chronic Hepatic Encephalopathy (RIFSYS)

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ClinicalTrials.gov Identifier: NCT02019784
Recruitment Status : Completed
First Posted : December 24, 2013
Last Update Posted : November 11, 2016
Sponsor:
Collaborator:
King's College London
Information provided by (Responsible Party):
King's College Hospital NHS Trust

Brief Summary:

Patients with cirrhosis are particularly prone to infection which is frequently a precipitant of hepatic encephalopathy, renal failure and circulatory collapse. Bacterial infections are of particular concern in patients with cirrhosis because they are poorly tolerated. Sepsis and associated endotoxaemia whereby bacteria produce inflammatory particles occur in approximately 40% of hospitalized patients with cirrhosis and is a major cause of death.

Gut-derived and blood-borne pathogens can induce an inflammatory response within the liver and spleen, which are the major organs that remove bacteria and their endotoxin (such as lipopolysaccharide - LPS and bacterial DNA itself) from the bloodstream. Several mechanisms have been identified and proposed in this process which depends upon a balance between the barrier functions of the gut and the 'detoxifying' capacity of the liver. People with established liver cirrhosis have been shown to have escape of endotoxin into the bloodstream produced by bacteria that reside in their intestines, which becomes more permeable or 'leaky'.

Gut dysfunction is defined by changes in the types of bacteria within the gut and in overall permeability allowing bacterial products which would otherwise be contained within the gut to travel into the bloodstream and lymphatic system with detrimental effects elsewhere in the body. This passage of bacterial products is termed bacterial translocation, and it's effects on the liver and general immune system can be then be measured.

It has now become recognised that certain types of white blood cells such as neutrophils and monocytes become dysfunctional and this predisposes to infection and may also have a more direct pathogenic role in hepatic encephalopathy. Thus neutrophil and monocytes may be a novel pharmacotherapeutic target in a condition where current therapies such as bowel aperients (e.g. lactulose) are inadequate. A therapeutic strategy utilising Rifaximin, a non-absorbable antibiotic, to modulate gut bacterial which produce ammonia, a chemical known to be important in the cause of hepatic encephalopathy, could potentially lower gut-derived systemic inflammation, endotoxaemia, infection and organ dysfunction in this population improving outcomes and prolonging transplant-free survival.

We therefore plan to test if Rifaximin positively affects markers of immune dysfunction in patients with liver cirrhosis experiencing chronic hepatic encephalopathy after 30 days of treatment, as our primary research question.

Positive results from this study would support further trials into the potential benefit of using Rifaximin to improve immune function, as well as reduce the recurrence of hepatic encephalopathy, in patients with liver cirrhosis.


Condition or disease Intervention/treatment Phase
Liver Cirrhosis Hepatoencephalopathy, Early Fatal Progressive Drug: Rifaximin-α Drug: Placebo Oral Tablet Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: A Placebo Controlled Single Centre Double Blind Randomised Trial to Investigate the Efficacy of Rifaximin Versus Placebo in Improving Systemic Inflammation and Neutrophil Malfunction in Patients With Cirrhosis and Chronic Hepatic Encephalopathy
Study Start Date : January 2015
Actual Primary Completion Date : June 2016
Actual Study Completion Date : October 2016


Arm Intervention/treatment
Active Comparator: Rifaximin-α
Rifaximin-α (TARGAXAN TM, manufactured by Alfa-Wasserman, Bologna, Italy) tablets - 550mg twice daily for 90 days
Drug: Rifaximin-α
Rifaximin-α will be compared to placebo with the various outcome measures assessed at baseline (pre-randomisation), and then at 30 days and 90 days.
Other Name: Targaxan (brand name)

Placebo Comparator: Placebo
Placebo tablets - 550mg twice daily for 90 days
Drug: Placebo Oral Tablet
Placebo Oral Tablet




Primary Outcome Measures :
  1. Rifaximin-α reducing neutrophil spontaneous oxidative burst ex vivo [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
    To test whether there is a reduction in spontaneous neutrophil oxidative burst of 50% compared to baseline (as measured by the Burstest which measures the spontaneous production of reactive oxygen species) 30 days following the start of rifaximin-α/placebo therapy.


Secondary Outcome Measures :
  1. Neutrophil bacteriocidal capacity [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
    An improvement in neutrophil bacteriocidal capacity as measured by the Phagotest which utilises opsonised E. coli at 30 and 90 days

  2. Reduction in systemic inflammation [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
    A reduction in systemic inflammation as measured by plasma endotoxemia, bacterial DNA quantification and plasma pro-inflammatory cytokine profile at 90 days.

  3. Improvement in neutrophil phenotype and function [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
    An improvement in neutrophil phenotype and function including baseline and LPS-induced toll-like receptor 4 expression and intracellular cytokine production at 30 and 90 days.

  4. Alterations in faecal microbiota at 90 days [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
  5. Reduction in intestinal permeability and changes in faecal biomarkers (calprotectin) at 90 days. [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
  6. Changes in urinary and plasma metabonomic profile [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
    Changes in urinary and plasma metabonomic profile as measured by proton MR spectroscopy at 90 days


Other Outcome Measures:
  1. Development of recurrent overt hepatic encephalopathy, organ failure and infection during the 90 day follow up [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]
  2. Improvement in Trails A and B neuropsychiatric test score at 30 and 90 days. [ Time Frame: Three time points: baseline before commencement of active drug/placebo, at 30 days and at 90 days ]


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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
Criteria

Inclusion Criteria:

  • Patients with established cirrhosis complicated by hepatic encephalopathy
  • For the purposes of this study a patient will be considered to have cirrhosis if they fulfil two out of the three diagnostic criteria of confirmatory liver histology, biochemistry and/or radiologic findings consistent with cirrhosis/portal hypertension, and
  • are presenting with chronic persistent overt hepatic encephalopathy (≥ grade 1) or with ≥2 episodes of overt hepatic encephalopathy in the previous 6 months.

Exclusion Criteria:

  • Age ≤18 or ≥75.
  • Evidence of disseminated malignancy.
  • Known coeliac or inflammatory bowel disease.
  • Evidence of intestinal failure, intestinal obstruction and / or previous bowel resection.
  • Pre-existing immunosuppressive states including HIV infection and chronic granulomatous diseases.
  • Anti-inflammatory drug use e.g non-steroidals and immunomodulatory drug use e.g. prednisolone and azathioprine.
  • Known hypersensitivity to rifaximin or rifamycin-derivatives
  • Already receiving concomitant oral or parenteral antibiotic therapy e.g norfloxacin.
  • Infection with clostridium difficile or stool testing positive for clostridium difficile toxin in the previous 3 months.
  • Pregnancy or breast feeding women

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 ClinicalTrials.gov identifier (NCT number): NCT02019784


Locations
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United Kingdom
King's College Hospital NHS Foundation Trust
London, United Kingdom, SE5 9RS
Sponsors and Collaborators
King's College Hospital NHS Trust
King's College London
Investigators
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Principal Investigator: Debbie Shawcross, MBBS PhD King's College London

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Responsible Party: King's College Hospital NHS Trust
ClinicalTrials.gov Identifier: NCT02019784     History of Changes
Other Study ID Numbers: KCH14-183_RIFSYS_V4.0
2013-004708-20 ( EudraCT Number )
First Posted: December 24, 2013    Key Record Dates
Last Update Posted: November 11, 2016
Last Verified: November 2016

Keywords provided by King's College Hospital NHS Trust:
Cirrhosis
Hepatic encephalopathy

Additional relevant MeSH terms:
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Fibrosis
Liver Cirrhosis
Brain Diseases
Hepatic Encephalopathy
Metabolism, Inborn Errors
Pathologic Processes
Liver Diseases
Digestive System Diseases
Central Nervous System Diseases
Nervous System Diseases
Liver Failure
Hepatic Insufficiency
Brain Diseases, Metabolic
Metabolic Diseases
Genetic Diseases, Inborn
Rifaximin
Anti-Bacterial Agents
Anti-Infective Agents
Gastrointestinal Agents