Randomised Controlled Trial of Mechanistic Effects of Rifaximin in Cirrhosis and Chronic Hepatic Encephalopathy
Condition: Liver Cirrhosis; Hepatoencephalopathy, Early Fatal Progressive
MeSH terms: Liver Cirrhosis; Hepatic Encephalopathy; Brain Diseases; Fibrosis
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      Overview

      The study will be designed and conducted as a double blind placebo controlled randomised
      controlled trial - Clinical Trial of an Investigational Medicinal Product.

      This study will be performed on patients referred to King's Liver Unit for further assessment
      and management of chronic overt hepatic encephalopathy (≥ Grade 1) or with ≥2 episodes of
      overt hepatic encephalopathy in the previous 6 months.

      The study will be performed on 50 patients with cirrhosis and chronic hepatic encephalopathy
      [25 Rifaximin and 25 placebo] aged between 18 and 75 years managed within the Liver Unit at
      King's College Hospital which is the largest tertiary Liver Transplant Centre within the UK.
      For the purposes of this study a patient will be considered to have cirrhosis if they fulfil
      2 out of 3 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.

      Patient demographics, clinical details (including Westhaven hepatic encephalopathy grade) and
      blood haematology, biochemistry (including venous ammonia), microbiology data and neutrophil
      function will be assessed and collated at baseline and following 30 and 90 days of Rifaximin
      therapy or placebo. Intestinal permeability will be assessed using the intestinal
      disaccharide test. Faecal microbiota analysis will be performed by deep pyrosequencing
      techniques and plasma endotoxemia will be measured (lipopolysaccharide levels) with bacterial
      DNA quantification as a marker of bacterial translocation. These will all be measured at 3
      time points: baseline and at 30 and 90 days after initiation of Rifaximin therapy or matching
      placebo.

      Investigations

      Patients will undergo intestinal functional tests within 7 days of recruitment, whereby they
      will be administered a test solution of not more than a cupful (150mls) of different types of
      non-absorbable sugars, which are drunk in liquid form by the participants. Prior to
      ingestion, baseline samples will be obtained as follows:

      i) blood samples - for analysis of intestinal & immune (dys)function, and metabonomic
      analysis ii) urine sample - for intestinal (dys)function & metabonomic analysis iii) stool
      sample - for faecal biomarker and microbiota analysis

      1v) ascitic sample (if clinically indicated) - surplus fluid will be analysed for bacterial
      translocation and immune (dys)function

      Once the test solution has been ingested, blood samples will be obtained via a cannula which
      is placed in a vein, usually in the arm, prior to the start of the test, to allow further
      sampling without causing discomfort to the patient. A total of 15 samples will be obtained
      over a 5 hour period, with intervals ranging between 20-30mins, of not more than 6mls per
      sample. At the end of the test, at a 5 hour interval, a further urine sample will be
      collected to allow for intestinal functional testing. This is exactly the same procedure as
      that specified in the approved 'The Gut-Liver Axis in Liver Disease & Liver Transplantation'
      study (REC ref: 12/LO/1417).

      Where participants are undergoing sampling of ascitic fluid for clinical reasons any fluid in
      excess of pathology's requirements will be analysed along with peripheral blood samples.
      Ascitic samples will only be taken from patients in whom a decision has been made to take
      these samples for clinical reasons (this decision will not be that of the investigator). No
      increased volume of such sample would be required.

      Clinical outcomes (development of recurrent overt hepatic encephalopathy, organ failure and
      infection) will be recorded for a total of 90 days.

      Analysis of samples - sites

      Blood, urine and ascitic samples will be analysed in the Institute of Liver Studies and
      King's College Hospital laboratories where various tests to determine intestinal and immune
      function will be undertaken. Stool samples will be analysed both at laboratories at King's
      College Hospital and at the Franklin-Wilkins Building, King's College London, where faecal
      biomarkers and faecal microbiota analyses will be performed, respectively. Metabolic analyses
      for metabonomic profiling will be carried out at Imperial College London (both at St Mary's
      Hospital and at the South Kensington Campus).

      Protocol

      A more detailed list of the tests and analyses to be performed is to be found in the
      protocol. Study-specific flow charts have also been provided for a step-by-step
      representation of the study, visually representing the study process including participant
      recruitment, randomisation, sampling protocols and analyses at the three time points and
      follow-up visits.
    

Intervention name(s): Rifaximin-α; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 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.; Placebo Oral Tablet
Other intervention name(s): Targaxan (brand name)
Intervention MeSH terms: Rifaximin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Cirrhosis; Hepatic encephalopathy