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
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
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||38 participants|
|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|
Active Comparator: Rifaximin-α
Rifaximin-α (TARGAXAN TM, manufactured by Alfa-Wasserman, Bologna, Italy) tablets - 550mg twice daily for 90 days
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
- 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.
- 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
- 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.
- 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.
- 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 ]
- 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 ]
- 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
- 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 ]
- 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 ]
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
|King's College Hospital NHS Foundation Trust|
|London, United Kingdom, SE5 9RS|
|Principal Investigator:||Debbie Shawcross, MBBS PhD||King's College London|