Probiotics In Colorectal Cancer Patients
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Design: double blind controlled randomized trial with a parallel design and 3 treatment
      groups Description of subjects: Patients admitted in study centers for colorectal surgery
      under laporoscopy and/or laparotomy.

      Product:

      Product 1: BB536 and LA1 (10E9) Product 2: BB536 and LA1 (10E7) Placebo: Maltodextrin Number
      of patients: enrolled subjects: n=33, ITT data set: n=31, PP data set: n=30

      Primary objective:

      Colonization (biopsy+stools) of each bacteria for one of the dose at D0 (surgical procedure)

      Secondary objectives:

        -  Influence of the probiotic bacteria on the gut microflora

        -  Modulation of the immune and inflammatory response

      Additional objectives:

        -  Investigate dose effect on La1 colonization

        -  Investigate the effect of La1 colonization, treatment without La1 colonization, and
           absence of treatment and La1 colonization on other bacteria and on immunological
           parameters
    

Detailed description: 
      BACKGROUND AND RATIONALE

      The administration of probiotic bacteria has been hypothesized to affect the composition of
      the intestinal microflora with reduction of pathogens in favour of non-pathogens. These
      events might modulate the immune and inflammatory responses, and the gut function.

      Experimental data demonstrated that the modulation of the mucosal function and enteric
      microflora by Lactobacillus plantarum reduces septic morbidity and mortality in animals. The
      administration of a mix of probiotics has been shown to be more effective than antibiotics to
      cure pouchitis in humans.

      Since patients undergoing colorectal operations have a high risk to develop infections due to
      the intraoperative contamination with enteral content and the occurence of bacterial
      translocation, changing the intestinal microflora, by giving lactobacilli may result in
      important advantages to reduce the risk of intraoperative complications and post operative
      sepsis.

      OBJECTIVES OF THE STUDY

      To evaluate if preoperative administration of mucosa reconditioning by probiotic may result
      in adherence to the colonic mucosa and change of the gut microflora, and may modulate the
      immune and inflammatory responses and gut function.

      EXPERIMENTAL DESIGN AND METHODS

      Overall Design and Control Methods Prospective, randomized, double-blind study design.

      Centers Departement of Surgery, San Raffaele University, Milan, Italy Departement of Surgery,
      San Gerardo Hospital, University of Milano-Bicocca, Italy

      Number of Subjects/assignment to Formula Groups In these departements about 50 patients are
      operated for colorectal disease yearly with laparoscopic approach. All these patients are
      potential candidates to partecipate in the study. It is expected that at least 80% of the
      patients will agree with partecipation, while during the course of the study about 25% of the
      partecipants are expected to withdraw. During the intake procedure the inclusion and
      exclusion criteria are checked. Eligible patients are informed about the objectives, the
      background and the design of the study. When the patient has given his or her consent to
      partecipate in the study, the preoperative status is assessed. The patients are then included
      in the study population and randomly assigned to one of the treatments. During surgery the
      intraoperative exclusion criteria are checked and non eligible patients excluded from further
      study. Each group consist of 15 patients in order to assure that at the end of the study 10
      patients per group will have completed the study.

      Groups:

      A: high dose of probiotics (active) compared with B: low dose of probiotics (control) and C:
      vehicle (placebo)

      Dosing Regimen ??

      Dosing Scheme:

      Preoperative day 5 through 1. Postoperative day 3 through 8. The three preparation will be
      give 3 times per day (6 hours interval).

      Duration of the study 6 months

      SCHEDULE OF ASSESSMENTS

      Day -6 -1 0 1 2 3 4 5 6 7 8

      S

      I I I I I MB MB MB MB MB GF GF GF GF GF GF GF GF GF GF

      S = select and inform patients I = immunological- inflammatory data MB = microbiological data
      GF= gastrointestinal function, fecal pH.

      Immunological- inflammatory data:

      DHR, lymphocyte subset (CD3, CD4, CD8, NK), IgA serum levels, CRP, IL-6, lactate.

      Number and subset of intestinal lymphocytes. In vitro response of lymphocytes and macropahges
      to mitogens and LPS.

      Microbiological data:

      Quantitative and qualitative culture of stool and colonic mucosa (aerobic and anaerobic total
      count, aerobic gram negative and positive count)

      • During surgery two mucosal samples will be collected for microscopic (adherence test) and
      microbiological evaluation of the presence of probiotic on the mucosa. Moreover, lymph nodes
      of the mesentery will harvested for microbiological analysis to assess translocation.

      Intraoperative parameters:

      Duration of surgery, blood loss, transfusion (amount and type), abdominal contamination.

      Gastrointestinal function:

      Clinical observation related to gastrointestinal symptoms and defecation pattern

      Concomitant Medication and Treatments All patients will receive an antibiotic prophylaxis
      with cefotetan 2gr 30 minutes before surgery (single shot) and bowel preparation with iso
      osmotic solution and enema the day before surgery.

      STUDY PARAMETERS

      Efficacy

      Primary Efficacy Parameters

        -  morphological and microbiological evaluation of the colonic microflora

        -  gastrointestinal function

      Secondary Efficacy Parameters

        -  immune and inflammatory response

        -  bacterial translocation

      Adverse event

      All adverse events encountered during the study will be reported on the Case Report Form. An
      adverse event is any adverse change from baseline, including intercurrent illness, wich
      occurs during the course of the study after treatment has started, whether considered related
      to treatment or not.

      Blinding and Randomization

      The three study formulae are blinded towards each other. Both researches and patients will be
      blinded.

      Randomization of patients into three groups is performed with the computer randomization
      program "Random". In this way patient numbers are assigned at random to the group "active
      formula", "placebo fromula" or "control formula.

      Within the three groups randomization is done in blocks of 10 patientnumbers. Per study group
      three letters are used which are assigned at random to the patientnumbers.

      The randomization list may be broken by them in case of an adverse event.

      Formulation and Packaging

      The formulation of the trial formulae will be in sachet

      Dispensing

      The investigator is responsible for storage of the study formulae during the time of the
      study. The sachets must be stored refrigerated until the time of handout. During the actual
      time that the patient takes the study formula no refrigeration of sachets is required. The
      investigator is responsible for the hand out of the study formulae in the order of the
      patientnumber.

      A dispensary record of the study formula issued and of any material returned will be kept.

      Preparation, Administration and Dosage of test formulae

      Route

      Before and after the operation the supplement is consumed orally.

      Administration protocol For 5 preoperative days in addition of a free choice of hospital
      food, and after surgery from day 3 to 8.

      Assessment of Compliance

      The investigator will take high care that patients comply with the conditions set for the
      study, in order to prevent unnecessary withdrawal because of non compliance.

      WITHDRAWAL OF SUBJECTS FROM STUDY

      Subjects have the right to withdraw from the study at any time for any reason. The
      investigator also has the right to withdraw subjects from the study in the event of
      intercurrent illness, adverse events, treatment failure after a prescribed procedure,
      protocols violation, cure, administrative reasons or other reasons. It is understood by all
      concerned that an excessive rate of withdrawal can render the study uninterpretable:
      therefore, unnecessary, withdrawal of subjects should be avoided. Should subjects decide to
      withdraw, all efforts will be made to complete and report the observation as thoroughly as
      possible. A complete final evaluation at the time of the patient's withdrawal should be made
      with an explanation of why the subjects was withdrawn from the study.

      If the reason for removal of a patient from the study is an adverse event or an abnormal
      laboratory test results, the principal specific event or test will also be recorded on the
      Case Report Form. In the event of an emergency when the patient's condition requires
      knowledge of the test treatment, the label may be opened to determine the nature of the test
      formula dispensed. ANY BROKEN CODE WILL BE CLEARLY JUSTIFIED AND EXPLAINED BY A COMMENT ON
      THE CASE REPORT FORM, along with the data on which the code was broken.

      REPLACEMENT POLICY

      Patients withdraw from the study will be replaced if necessary.

      CRITERIA FOR EXCLUSION OF SUBJECTS' DATA FROM ANALYSES OF STUDY PARAMETERS

        -  Intra operative exclusion

        -  Extensive evidence of non compliance.

      Hypothesis Testing

      H0: Probiotic bacteria do not affect the microbiology of the gut mucosa and stools
      gastrointestinal function, immunological or inflammatory parameters compared with control or
      placebo.

      H1: Probiotic bacteria significantly diminishes the number of adhrent and stool pathogens
      improves gastrointestinal function and/or immunological parameters and/or inflammatory
      parameters compared with control or placebo.
    

Intervention name(s): Probiotics (La1, BB536); probiotics (La1, BB536); placebo
Intervention type(s): Procedure; Biological; Biological
Intervention description(s): Maltodoxtrin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Probiotics; La1; BB536; Colorectal surgery; Intestinal immunity; Dendritic cells; Lymphocyte; Microbiota