Bovine Colostrum for Patients With Non Alcoholic Fatty Liver Disease
Condition: Nonalcoholic Steatohepatitis; Fatty Liver Disease
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Trial Synopsis: Bovine Colostrum for patients with non alcoholic fatty liver disease (NAFLD).

      Design: This is a single-arm, open-label, before-and after exploratory trial of 30 days of
      Bovine Colostrum Powder (BCP) to improve NAFLD and the metabolic syndrome.

      Duration: 8 weeks per subject.

      Sample Size: 30 subjects.

      Population: Patients with biopsy proven NASH (NAS of > 4) and an ALT level of ≥ 30 (U/L).

      Regimen Study treatment will consist of BCP, three 1.2 g oral tablets (equivalent to 600 mg
      of BCP each) for 4 weeks, from cows immunized to insulin. Patients will be followed for
      safety monitoring for an additional 4 weeks.
    

Detailed description: 
      1. HYPOTHESIS AND STUDY OBJECTIVES

           1.1. HYPOTHESIS

           Ingestion of bovine colostrum powder (BCP) from cows immunized to insulin will improve
           non alcoholic steatohepatitis and the metabolic syndrome in patients suffering from
           these conditions

           1.2. PRIMARY OBJECTIVES

           1.2.1 To determine the efficacy of BCP in improving liver enzyme levels in patients with
           NASH.

           1.2.2 To determine the safety of the administration of oral BCP to patients with NASH.

           1.3. SECONDARY OBJECTIVES

           1.3.1. To determine whether the administration of BCP will improve the metabolic
           syndrome in patients with NASH (namely insulin resistance).

        2. INTRODUCTION

           2.1. BACKGROUND

           2.1.1. Nonalcoholic steatohepatitis.

           Nonalcoholic steatohepatitis or NASH is a common, often "silent" liver disease which
           affects about 2%-5% of Americans4-6. NASH is strongly associated with the metabolic
           syndrome, diabetes type-2 and obesity and can lead to cirrhosis, HCC, liver
           transplantation or death. The only mean for proving a diagnosis of NASH and separating
           it from simple fatty liver is liver biopsy (an invasive procedure which carries a
           certain degree of risk). Currently, there is no effective treatment for NASH7.

           2.1.2. The effect of Hyperimmune Bovine Colostrum on NASH

           Regulatory T cells (Tregs) are recognized as an important immunomodulatory component of
           the adaptive immune system. Immune dysregulation may lead to chronic inflammation,
           triggering chronic insulin insensitivity and non-alcoholic steatohepatitis (NASH). The
           role of Tregs in the adipose tissue in the regulation of NASH was not previously
           studied. Aim: To assess the effects of Tregs stimulation on hepatic injury and insulin
           resistance in NASH. Methods: Leptin deficient Ob/Ob mice were fed for 4 weeks with
           colostrum derived solutions (CDS) enriched with anti insulin specific antibodies
           (AIS-CDS, Immuron, Australia), or with purified anti insulin specific CDS (PAIS-CDS).
           The immunologic effect on the adipose tissue was determined by flow cytometry performed
           on the central adipose tissue and its stromal vasculature (SV), and compared with the
           effect on immune system of the liver and the spleen. Hepatic injury and insulin
           resistance was determined by glucose tolerance tests (GTT) and liver enzymes. Results:
           Oral administration of anti-insulin antibodies promoted the SV CD4+CD25+FoxP3+ cells
           (13.05 vs. 27.94 p=0.01). Treatment was associated with a decrease of the CD4+IL17+
           lymphocyte subset in the adipose tissue (87.89 vs. 12.93, p<0.01), the SV (61.86 vs.
           14.99, p<0.01), and in the liver (40.18 vs. 2.66, p<0.01). The liver CD8+CD25+FoxP3+
           lymphocyte subset was significantly increased (0.36 vs. 2.39, p<0.05). The CD4/CD8+
           lymphocyte ratio in the adipose tissue showed a mirror effect to that of the spleen and
           liver suggesting an opposite effect on lymphocyte trapping. Promotion Tregs in the
           adipose tissue was accompanied by a marked improvement in insulin resistance manifested
           by decreased glucose and insulin serum levels, and improved glucose tolerance test
           results (a decrease of 45%, in the area under the curve 23355 vs. 42448, in treated vs.
           controls, respectively), along with decreased liver enzymes (ALT levels decreased from
           743.4 to 379.8 IU, p<0.05; and AST from 770.5 to 299IU, in controls vs., treated
           respectively, p=0.07) without a change in body weight. Conclusions: The immune system of
           the adipose tissue plays an important role in the regulation of the metabolic syndrome.
           Decreasing TH17 in the liver, adipose tissue and SV, along with promotion of
           CD4+CD25+FoxP3+ and CD8+CD25+FoxP3+ Tregs (in the SC and liver respectively), by oral
           administration of anti insulin CDS offers a new treatment modality for NASH and insulin
           resistance, making Tregs in adipose tissue as a new therapeutic target for alleviation
           of the liver damage in NASH.

           2.1.3. BCP Has Been Shown to Be Safe and Well-tolerated in Humans

           Over 80,000 packets of Anadis tabletted BCP product with the same active component has
           been sold in Australia over 4 years. There have been no reported adverse events reports
           to Anadis. BioGard itself as a higher dose separate product was approved in 2008.

           Risk of microbiological contamination: The colostrum in the product is pasteurized;
           strict procedures minimize risk of contamination, and tablet batches are tested for
           yeast, mold, coliform bacteria, Enterobacteriaceae, staphylococci, Salmonella, and
           Listeria. The cows for colostrum production are sourced only from bovine spongiform
           encephalopathy (BSE)-free countries. Additionally, milk products are considered to have
           no detectable infectivity and are considered unlikely to present any risk if sourced
           from healthy animals under the same conditions as milk collected for human consumption.

           Lactose intolerance: Bovine colostrum extract generally contains <10% lactose, compared
           with about 50% in normal skim milk powder; therefore, lactose intolerance is unlikely to
           be a major safety problem. Clinical signs can be expected in susceptible humans given
           5-10g of lactose (Thorn et al, 1977). At a dose of bovine colostrum extract of 10g a day
           (2.8g more than the dose proposed in this study), a maximum of 1 g would be lactose.

           Side effects. No cases of death have ever been reported in studies of BCP. While the
           typical dose is 10g/day [8-10] doses as high as 10 g four times daily have been
           studied[11]. Adverse reactions have been few in number and slight in severity. In most
           clinical studies on the efficacy of bovine colostrum there have been no demonstrable
           adverse effects[9, 10, 12-15]. When they have occurred, they have mostly consisted of
           nausea, emesis, flatulence, and mild diarrhea[8, 11, 14, 16, 17]. In one study,
           transient moderate elevations in serum levels of hepatic transaminases were observed in
           volunteers who received bovine immunoglobulin concentrates prepared against E. coli
           (5/10) and rotavirus (2/10). This effect was attributed to diets high in protein
           provided at the hospital (13). More recently, bovine colostrum was well-tolerated in
           HIV-infected persons for the treatment of HIV-associated diarrhea (18).

           Colostrum administration should be avoided in person allergic to cow's milk.

        3. STUDY DESIGN

           This is a single-arm, open label, before-and-after exploratory trial to evaluate the
           effect of 4 weeks of BCP administration on serum liver enzymes and the metabolic
           syndrome in patients with NASH. Candidates will be identified from among the patients
           treated in the department of medicine and liver unit of the Hadassah Hebrew University
           Medical Center and will be asked to sign an approved informed consent from before any
           study activities are initiated. Participants will be followed on study with weekly
           visits as well as for an additional 4 weeks after concluding treatment to assess safety.

        4. SELECTION AND ENROLLMENT OF SUBJECTS

      4.1. INCLUSION CRITERIA

      4.1.1. Biopsy proven NASH (NAS score ≥ 4) 4.1.2. Serum ALT levels ≥ 30 (U/L) 4.1.3. Age 18-65
      4.1.4. Treatment of diabetes by up to 2 oral medications, with stable doses for 2 months.

      4.1.5. If participating in sexual activity that could lead to pregnancy, the study volunteer
      must agree that two reliable methods of contraception will be used simultaneously while
      receiving the protocol-specified medication and for 1 month after stopping the medication.

      NOTE: Hormonal-based methods alone are not sufficient. At least two of the following methods
      MUST be used appropriately unless documentation of menopause, sterilization, or azoospermia
      is present:

        -  Condoms (male or female) with or without a spermicidal agent. - Condoms are recommended
           because their appropriate use is the only contraception method effective for preventing
           HIV transmission

        -  Diaphragm or cervical cap with spermicide

        -  IUD

        -  Hormonal-based contraception

      Study subjects who are not of reproductive potential (girls who have not reached menarche or
      women who have been post-menopausal for at least 24 consecutive months or have undergone
      hysterectomy and/or bilateral oophorectomy are eligible without requiring the use of
      contraceptives. Written or oral documentation communicated by clinician or clinician's staff
      is required by one of the following:

        -  Physician report/letter

        -  Operative report or other source documentation in the patient record (a laboratory
           report of azoospermia is required to document successful vasectomy)

        -  Discharge summary

        -  Laboratory report of azoospermia

        -  FSH measurement elevated into the menopausal range as established by the reporting
           laboratory.

      4.1.6. Ability and willingness of subject or legal guardian/representative to provide
      informed consent.

        1. EXCLUSION CRITERIA

      i. Pregnancy or Breast-Feeding

      ii. Continuous use of the following medications for more than 3 days within 30 days of study
      entry:

        1. Immunosuppressives

        2. Immune modulators

        3. Systemic glucocorticoids

        4. Anti-neoplastic agents

        5. Insulin iii. Active drug or alcohol use or dependence that, in the opinion of the site
           investigator, would interfere with adherence to study requirements.

      iv. Serious illness requiring systemic treatment and/or hospitalization within 30 days prior
      to entry.

      v. Operation within the previous 3 months. vi. A serious infectious, cardiac, pulmonary, or
      nephrological disease vii. Allergic to cow milk or lactose intolerant.

      2. STUDY TREATMENT

      a. REGIMEN, ADMINISTRATION AND DURATION

      i. Per-protocol treatment regimen

      Subjects will receive treatment with BCP 1.8 grams (3 capsules) for 4 weeks and will then be
      monitored off study treatment for an additional 4 weeks.

      ii. Study treatment modifications

      Dose reductions will not be allowed. All study drug modifications will be documented and
      recorded.

      b. STUDY PRODUCT FORMULATION AND PREPARATION

      The study medication is supplied at tablets packaged individually in blister packs. Each 1.2
      g tablet contains 600 mg of freeze-dried BCP from cows immunized to insulin as the only
      active component, in combination with excipients including silica colloidal anhydrous,
      magnesium stearate, microcrystalline cellulose and calcium carbonate. The product can be
      stored at room temperature and has a shelf life of 5 years.

      c. PHARMACY: PRODUCT SUPPLY, DISTRIBUTION, AND ACCOUNTABILITY

      i. Study product acquisition/distribution

      BCP will be supplied by Immuron, and will be stored and dispensed by the research pharmacies
      at the Hadassah Hebrew University Medical Center.

      ii. Study product accountability

      The site pharmacist is required to maintain complete records of all study products.

      d. CONCOMITANT MEDICATIONS

      i. General guidelines

      There are no specific protocol-imposed restrictions on concomitant medications, other than
      stipulated in the inclusion/exclusion criteria. Nonetheless, whenever a concomitant
      medication or study agent is initiated or a dose changed, investigators will review the
      concomitant medications' and study agents' most recent package inserts, investigator's
      brochures, or updated information from on-line sources to obtain the most current information
      on drug interactions, contraindications, and precautions.

      ii. Prohibited medications

      Use of the following medications for more than 3 days within 30 days of study entry: Insulin,
      immunosuppressives, immune modulators, anti-neoplastic agents, glucocorticoids.

      e. ADHERENCE ASSESSMENT

      At each visit, participants will be queried about the number of doses of study medication
      missed since the last visit.
    

Intervention name(s): Bovine colostrum powder
Intervention type(s): Dietary Supplement
Intervention description(s): Study treatment will consist of BCP, three 1.2 g oral tablets (equivalent to 600 mg of BCP each) for 4 weeks, from cows immunized to insulin. Patients will be followed for safety monitoring for an additional 4 weeks.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: NASH; fatty liver disease; colostrum