Intestinal Decontamination With Rifaximin. The Inflammatory and Circulatory State in Patients With Cirrhosis
Condition: Liver Cirrhosis; Ascites
MeSH terms: Liver Cirrhosis; Fibrosis; Ascites
Study type: Interventional
Phase: Phase 4

Summary: 
      This investigational trial will be assessing the effect of rifaximin on pathophysiology and
      haemodynamics in the patient with liver cirrhosis, and addressing the effect of rifaximin on
      several organs on marker level. The molecular and physiological effects of rifaximin will be
      explored.

      The investigators hypothesize that intestinal decontamination with rifaximin in patients with
      cirrhosis and ascites will interrupt bacterial translocation from the gut, diminish the
      following inflammatory response, prevent splanchnic vasodilatation and portal systemic
      contraction and thereby reduce the risk clinical complications to cirrhosis.

      If rifaximin can correct small intestinal bacterial overgrowth and demonstrate improvement in
      liver haemodynamics, renal function and systemic dynamics, then these effects may contribute
      to the overall well-being of the patient and prevent complications to the underlying
      cirrhosis such as risk of infections, progression of disease, and admission to hospital.
    

Detailed description: 
      Background:

      Ascites is a frequent complication of cirrhosis, occurring in 50% of patients and is
      associated with 50 % mortality in two years.

      Bacterial infections in patients with cirrhosis are frequent during hospitalization and is an
      important precipitating event for the development of renal failure and hepatorenal syndrome,
      hepatic encephalopathy and possibly also variceal bleeding. High Child-Pugh Score, variceal
      bleeding and low ascitic fluid protein levels are associated with high risk of infection.

      The infections are mainly triggered by gut bacterial translocation, the migration of
      microorganisms from the intestinal lumen to mesenteric lymph nodes or extra-intestinal sites.
      Some studies have shown derangements in the gut micro ecology of patients with liver
      cirrhosis, partly due to a decrease in small intestinal motility, which could cause small
      intestinal bacterial overgrowth. Combined with structural and functional alterations of the
      intestinal mucosa and deficiencies in defense mechanisms, this bacterial overgrowth
      contributes to bacterial translocation.

      Circulating bacterial DNA is a marker of bacterial translocation that may enhance endothelial
      dysfunction and predict a poor outcome in cirrhosis and ascites. Selective gut
      decontamination prevents spontaneous bacterial infections and improves survival in advanced
      cirrhosis, such as in variceal bleeding and in patients with spontaneous bacterial
      peritonitis (SBP).

      Patients with advanced cirrhosis are, apart from having portal hypertension, characterized by
      a marked systemic vasodilatation, an increased cardiac output and a low central blood volume.
      This could be due to raised levels of endotoxins in the blood and the induced inflammatory
      response.

      This induces increased expression and activation of nitrogen oxidase synthase leading to
      excessive NO production and further vasodilatation. Moreover, high levels of cytokines
      (LPS-BP, Interleukin-6 and TNF-a), is associated with a lower systemic vascular resistance
      (SVR) and a higher cardiac output (CO) in cirrhotic patients.

      In decompensated cirrhosis several vasoactive hormones are activated to counterbalance this
      vasodilatation.

      In animal studies, it has been shown that oral antibiotics might reduce bacterial
      translocation and the vasodilatation in the splanchnic vasculature.

      Rifaximin seems to be an attractive alternative that exerts a broad-range of antimicrobial
      activity including gram-positive bacteria. Rifaximin induces less bacterial resistance and
      acts predominantly in the small intestine, the site of bacterial overgrowth in cirrhosis.

      Rifaximin has been shown to reduce the risk of hepatic encephalopathy, with less side effects
      than traditional lactulose treatment.

      The hepatic venous pressure gradient (HVPG) is a marker of severity of cirrhosis and has
      important prognostic value in the assessment of risk of complications to cirrhosis. An
      uncontrolled study has suggested that rifaximin may decrease HVPG(8). A recently published
      pilot study has furthermore suggested, that rifaximin might improve systemic haemodynamics by
      decreasing cardiac output and also increasing glomerular filtration rate (GFR).

      Aim:

      This novel, investigational trial will be assessing the effect of rifaximin on
      pathophysiology and haemodynamics in the patient with liver cirrhosis, and addressing the
      effect of rifaximin on several organs on marker level. We will explore the molecular and
      physiological effects of rifaximin rather than confirming evidence of its already known
      beneficial effects.

      Hypothesis:

      We hypothesize that intestinal decontamination with rifaximin in patients with cirrhosis and
      ascites will interrupt bacterial translocation, diminish the following inflammatory response,
      prevent splanchnic vasodilatation and portal systemic contraction and thereby reduce the risk
      of clinical complications to cirrhosis.

      Hence, rifaximin:

        1. Will decrease portal pressure, measured as the hepatic venous pressure gradient (HVPG).

        2. Will ameliorate the peripheral and splanchnic vasodilatation by a decrease in cardiac
           output (CO) and an increase in arterial blood pressure and systemic vascular resistance
           (SVR). These effects should also be reflected by a trend towards normalization of
           vasoactive hormones.

        3. Will improve renal function expressed as an increase in glomerular filtration rate.

        4. Will down regulate markers of inflammation expressed as a decrease in proinflammatory
           cytokines (i.e. TNF-a and interleukins) and high sensitivity CRP.

        5. Attenuate markers of infection, expressed by bacterial DNA and lipopolysaccharide
           binding protein (LPS-BP).

        6. Inhibit small intestinal bacterial overgrowth as measured by breath tests and intestinal
           transit-time in a subgroup of patients.

      Methods:

      Trial design:

      This is a randomized, placebo controlled clinical trial. We aim to randomize in the relation
      2:1, including 38 patients for rifaximin treatment and 19 patients for placebo. These numbers
      are based on power calculations demanding a power of 80% probability of a true finding.

      Trial participants:

      Our trial population will consist of adult, legally competent patients with liver cirrhosis
      Child-Pugh score B or C and ascites. Patients that fulfill inclusion criteria will be
      recruited from hospitals in the capital region of Denmark.

      The patients will be referred to Hvidovre hospital for liver vein catheterisation, a
      diagnostic procedure included in the standard diagnostic programme for liver cirrhosis.

      Initiation of trial:

      The patient is admitted to hospital and baseline investigations are performed, including
      clinical examination, blood samples, glucose breath test, blood and urine culture, ascites
      puncture, faecal samples, and examination of continuous reaction time.

      On the second day of admission liver vein catheterization and assessment of renal function is
      performed and samples of blood from femoral artery and hepatic vein is drawn.

      Then the patient is randomized to tablet rifaximin treatment or placebo for 28 days.

      During the period of treatment the patient is closely monitored by an outpatient visit and by
      contact on telephone.

      End of trial:

      At the end of the trial period, patients are re-hospitalized and the investigational
      programme is repeated. After six months a register follow up

      Time schedule:

      November 2012: Initiation of trial and enrollment of first patients. November 2014:
      Enrollment of the last patients and investigations. May 2015: End of follow up and trial
      lock. Spring 2015: Assessments and analysis of first data. Summer/Autumn 2015: Publication of
      results.

      Collaborating units:

      Department of Gastroenterology, Department of Clinical Physiology and Nuclear medicine, Unit
      of Radiology and Diagnostic Research and Department of Clinical Biochemistry, Clinical
      Research Centre, all Copenhagen University Hospital Hvidovre.

      Rifaximin tablets and placebo tablets are delivered by Norgine Denmark A/S, free of costs,
      and labelled and packed by Region Hovedstadens Apotek.

      The Good Clinical Practice Unit, Capital Region of Denmark, monitors the trial. Patients are
      screened for inclusion at Departments of gastroenterology, and internal medicine at hospitals
      within the Capital Region of Denmark

      Implications of the trial:

      If rifaximin can correct small intestinal bacterial overgrowth and demonstrate improvement in
      liver haemodynamics, renal function and systemic dynamics, then these effects may contribute
      to the overall well-being of the patient and prevent complications to the underlying
      cirrhosis such as risk of infections, progression of disease, and admission to hospital.

      It is possible that trial participants randomized to rifaximin treatment will experience an
      improvement in both kidney function and bowel function, with less distress, flatulence or
      diarrhea. It is also possible that this group of patients will have fewer complications to
      their cirrhosis, such as fewer admissions to hospital, fewer infections and a smaller risk of
      variceal bleeding and SBP.

      It is also a possibility, but not certain, that participants randomized to rifaximin will
      experience improvement in their mental status and their general condition, for example less
      fatigue, better appetite and more strength.

      Participation in this trial contributes to new knowledge about the foundations and scientific
      background that causes the serious complications to liver cirrhosis, thus enabling us to
      improve diagnosis and treatment of this disease and its comorbidity.

      This is a pathophysiological and investigational trial, and besides the mentioned benefits
      for the participant, he or she will also contribute to the possible development of new
      treatment regimens for liver cirrhosis.

      If intestinal decontamination with rifaximin alleviates the mechanism leading to
      decompensation and its complications it may potentially have a clinical impact in advanced
      cirrosis beyond preventing recurrent hepatic encephalopathy. The aspects are prevention of
      spontaneous bacterial peritonitis in patients at risk of this disease, and potentially
      prophylaxis for patients with biochemical signs of bacterial translocation.
    

Intervention name(s): Rifaximin; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 550 mg two times daily for 28 days
Other intervention name(s): Xifaxan
Intervention MeSH terms: Rifaximin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Decompensated liver cirrhosis; Ascites; Haemodynamics; Small intestinal bacterial overgrowth; Pathophysiology