Evaluation of Serum-Derived Bovine Immunoglobulin Protein Isolate in Subjects With Decompensated Cirrhosis With Ascites
Condition: Cirrhosis of the Liver; Ascites; Spontaneous Bacterial Peritonitis
MeSH terms: Peritonitis; Liver Cirrhosis; Fibrosis; Ascites
Study type: Interventional

Summary: 
      This protocol represents an open-label pilot study to assess whether oral administration of
      SBI in subjects with decompensated cirrhosis with ascites can lead improvements in the
      management of the disease. The impact of SBI therapy will be based on changes to markers of
      bacterial translocation, gut barrier damage, and inflammation as well as the impact on rates
      of SIBO. Study subjects will be given one packet of EnteraGam, each packet containing 5.0 g
      SBI, twice daily for 8 weeks.
    

Detailed description: 
      The Gut Barrier and Pathological Bacterial Translocation: The "Achilles Heel" of Hepatology

      The intestinal wall is a complex barrier that exists between humans and their environment.
      Inside the intestinal lumen, the commensal flora exposes the epithelium to nearly 100
      trillion bacteria.1 This epithelial layer provides a surface area of 400 square meters, lined
      with tight junctions that prevent the translocation and paracellular transport of luminal
      antigens including bacteria.2 In addition to this mechanical barrier, the wall of the
      intestine is lined with mucosal immune defenses, notably gut-associated lymphoid tissue
      (GALT), the largest immunologic organ in the body.1 Under normal circumstances, this
      functional and efficient barrier prevents entry of bacteria from the outside world.

      Failure of this intestinal barrier, along with an increased rate of pathological bacterial
      translocation, has been shown to be associated with increasing severity of liver disease and
      the development of decompensated cirrhosis.3 Factors thought to contribute to bacterial
      translocation in subjects with cirrhosis include small intestinal bacterial overgrowth
      (SIBO), which is known to have an increased prevalence in subjects with cirrhosis compared to
      those without4, hyperdynamic portal status, alterations in the GALT tissue altering the
      immune response, and impaired intestinal permeability seen in subjects with ascites.3 This
      increased permeability is believed to result from structural abnormalities in the intestinal
      mucosa, including widening of intercellular spaces, edema, inflammation, and vascular
      congestion.5-7

      Failure of the intestinal barrier is routinely thought to play an important role in the
      natural course of cirrhosis, so much so that this has been referred to as hepatology's
      "Achilles heel."8 Pathologic bacterial translocation across the intestinal epithelium is
      suspected to impact the clinical course of liver cirrhosis by triggering encephalopathy,
      hepatic failure, and hepatorenal syndrome, in addition to having a long known role as an
      underlying mechanism of the development of spontaneous bacterial peritonitis (SBP) and other
      bacterial infections in this population.9 Given that SBP is associated with high mortality
      rates ranging from 10-42%,10 and that subjects with cirrhosis have increased susceptibility
      to infections, antibiotic prophylaxis has emerged as a widely accepted strategy in subjects
      at increased risk for bacterial translocation, such as those with active gastrointestinal
      bleeding and low protein content ascites. However, this therapeutic strategy has the
      potential of selecting resistant bacterial strains and increasing the risk of subjects
      developing Clostridium difficile associated diarrhea.

      Alternative methods for the prevention of SBP and bacterial infections in subjects with
      cirrhosis could prove to be very beneficial in reducing mortality and preventing the
      development of antibiotic resistance. In particular, preventing pathological bacterial
      translocation at the intestinal barrier could be highly effective.

      Serum-Derived Bovine Immunoglobulin: a Logical Therapy to Improve Gut Barrier Function

      Immunoglobulins taken orally are known to play a prominent role in health and development
      given the known benefits of human milk and colostrum, a form of milk produced by mammals
      which contains significant amounts of antibodies.11 Recognition of the essential nature of
      these antibodies led to the development of commercial plasma-derived protein concentrates
      containing immunoglobulins, which have been used for decades in animal husbandry to promote
      growth and manage intestinal inflammation in immune-compromised young animals.12-14

      Serum-derived bovine immunoglobulin / protein isolate (SBI) is a novel medical food marketed
      under the brand name, EnteraGam®. This product is currently indicated (see EnteraGam package
      insert for details) for the clinical dietary management of several forms of enteropathy,
      including diarrhea predominant irritable bowel syndrome (IBS-D) and intestinal bowel disease
      (IBD). While the term, enteropathy, refers to any pathology or disease of the intestines,
      known histological features can include blunting of intestinal villi, increased
      intra-epithelial lymphocytes causing reduced absorptive capacity, and increased gut
      permeability.12 In cases of enteropathy, a combination of factors including altered gut
      microbiota, increased intestinal inflammation, and worsening gut barrier dysfunction are
      known to increase the risk of bacterial translocation.12 Each of these factors is a potential
      target for SBI. In terms of altered gut microbiota, extensive literature has demonstrated
      broad bacterial antigen neutralizing capacity of ingested immunoglobulins.15-17 Likewise,
      many non-clinical studies have shown that SBI can reduce intestinal inflammation by
      decreasing mucosal cytokines and dampening immune activation.18-19 Furthermore, the available
      data suggest that oral immunoglobulin therapy benefits tight-junction integrity in epithelial
      barriers, as evidenced through increased transepithelial electrical resistance and reduction
      in radiolabeled 14C-inulin permeability across the intestine.19

      To date, there is a large body of evidence showing that serum- or plasma-derived bovine
      immunoglobulin preparations can effectively manage the symptoms and harmful effects of
      enteropathy in both animals and humans. Animal studies include data regarding barrier
      function and nutrient absorption in animals including mice, rats, and pigs.12 Studies
      performed in children show promising results in terms of weight gain and the underlying
      problem of malabsorption.22-23 Among adults, preliminary studies show promising results of
      SBI in the management of HIV enteropathy in addition to diarrhea-predominant Irritable Bowel
      Syndrome.24,25 Collectively, there is strong evidence to support the theory that ingestion of
      oral immunoglobulins such as SBI could reduce the risk of bacterial translocation in patients
      with cirrhosis, namely by neutralizing bacterial antigen in the intestine, reducing
      intestinal inflammation, and decreasing permeability of the gut barrier.
    

Intervention name(s): Medical food, EnteraGam (Serum-Derived Bovine Immunoglobulin)
Intervention type(s): Other
Intervention description(s): Visit 1, screening (Day 0): At this visit, the investigators of the study will:
Obtain demographic information, as will past medical history and medications.
Perform a physical examination.
Collect samples for labs
Administer the Chronic Liver Disease Questionnaire (CLDQ)
Perform a lactulose breath test
From Day 0 to 8 weeks: subjects will take the medical food twice daily
Visit 2, Week 4 (Day 28 +/- 3): At this visit, the investigators of the study will:
Perform a physical examination
Collect and record returned investigational product
Dispense investigational product and instruct again regarding use
Record any adverse events
Visit 3, Week 8 (Day 56 +/- 3): At this visit, the investigators of the study will:
Perform a physical examination.
Collect samples for labs
Administer the Chronic Liver Disease Questionnaire (CLDQ)
Perform a lactulose breath test
Other intervention name(s): Serum-Derived Bovine Immunoglobulin
Intervention MeSH terms: Immunoglobulins; Immunoglobulins, Intravenous; Antibodies
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Supportive Care
Keywords: Cirrhosis; Ascites; SBP