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

• Status: Completed
• Trial end date: 2016-10-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: King's College Hospital NHS Trust
• Collaborator: King's College London
• Treatments: Rifamycins; Rifaximin

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