Fiber to Reduce Colon Cancer in Alaska Native People
Condition: Colon Cancer
MeSH terms: Colonic Neoplasms
Study type: Interventional

Summary: 
      Alaska native people (AN) have the highest recorded incidence and death rate from colon
      cancer in the world (>90:100,000). We hypothesize that the AN, despite their high consumption
      of anti-inflammatory and antineoplastic n-3 fish oils, are at increased risk of colon cancer
      because of colonic butyrate deficiency resulting from their remarkably low consumption of
      fiber-containing foods. We hypothesize that fiber supplementation of their usual diet will
      result in a bloom of butyrate producing microbes in the colon, resulting in increased
      butyrate production, which will suppress their high microbial secondary bile acid production,
      antagonize the actions of other food (smoked fish) and environmental carcinogens (tobacco,
      alcohol), and interact with the high circulating levels of n-3 fish oils to suppress colonic
      inflammation and cancer risk. In order to investigate this, we will conduct a randomized
      double-blinded 4-week clinical trial in up to 100 randomizable healthy, middle-aged AN
      undergoing screening colonoscopy, with the objective of obtaining 60 completed interventions.
      The interventions will consist of either a high-dose soluble fiber supplement given as a
      drink, together with their usual diet which currently contains about 15g total fiber/d, or to
      a control digestible starch drink plus their usual diet. The primary endpoint will be a
      clinically significant reduction in Ki67 proliferative colonic mucosal biomarkers of cancer
      risk. Microbiome and metabolome mechanisms responsible for the anticipated changes in mucosal
      biomarkers will also be investigated. Our results in extreme risk AN will be further
      evaluated by comparison to similar measurements previously made in minimal risk rural
      Africans and intermediate risk African Americans. Our results will be used to provide the
      scientific basis for a definitive large-scale high-fiber supplementation study (to achieve
      >50g total fiber/d) to suppress adenomatous polyp recurrence following colonoscopy.
    

Detailed description: 
      Randomization for the double blind, placebo controlled, clinical trial: Recruitment will
      continue until 60 volunteers have completed the intervention study. Based on previous
      experience with similar studies, we anticipate 20% of screened patients to be ineligible or
      drop out, which means, so we plan on consenting and screening approximately 100 potential
      participants. Baseline data from these participants will be retained. Individuals will be
      randomized via minimisation (based on age, sex, polypectomy, high fish consumption, and BMI -
      factors that might influence microbiota composition and function)) to either the resistant
      starch (RS) group or the control digestible starch (DS) group upon completion of the
      Stabilization Period.

        1. RS Group: Participants will continue with their usual diet plus fiber supplement given
           as a daily dose of 70g high-amylose maize starch (HAM-RS, HI-MAIZE®260: Ingredion
           Incorporated, Bridgewater, NJ), which contains 42g of type 2 resistant starch, for 4
           weeks. Data from previous studies[69] suggests that their usual diet will contain
           approximately 13g dietary fiber/day, chiefly insoluble, indicating that total fiber
           intake would be approx. 55g/d. Supplements will be pre-weighed out in batches from the
           same source and kept in airtight containers. The supplement may be taken as a single or
           divided dose dissolved in 250ml water, low fat milk, or orange juice

        2. DS (Control) Group participants will continue on their usual diet, plus 70g of fully
           digestible starch (waxy corn starch comprised of amylopectin, AMIOCA® corn starch,
           Ingredion Incorporated, Bridgewater, NJ ) weighed out, analyzed, and prepared as
           previously. The RS and control supplements will appear and taste similar, allowing for
           coding and distribution in a double-blind fashion. The supplements will be equicaloric.

      Interventions will include fecal and colonic content sampling for measurement of the
      microbiome and metabolome, and flexible sigmoidoscopy to obtain mucosal biopsies before and
      after the dietary supplementation.

      Monitoring During the Clinical Trial: This will follow the scheme laid out on Figure 7. On
      day 0, participants will visit the clinic and will be asked to save their first fecal sample
      using our standard operating procedure developed and proven to be effective in our last
      study. They will then be given their first supplement drink made up in their vehicle of
      choice, and taken with a standard meal provided by the diet kitchen. During the trial, they
      will be instructed on the use of a simple diary to be completed at home. This will record the
      major food items consumed each day, the timing and completion of drink supplements, as well
      as the bowel function questionnaire to assess daily GI tolerance, i.e. abdominal discomfort,
      distension, gas, bowel frequency, nausea, vomiting. They will be asked to return to the
      clinic for a follow-up appointment on day 7, 14 and 21 in order to repeat the fecal and
      breath tests described above. At the same time, body weight will be monitored using one
      scale. At the end of 4 weeks, participants will be asked to return to the clinic for repeat
      of the colonic sampling performed at baseline.
    

Intervention name(s): 70g of fully digestible starch amylopectin corn starch; Resistant starch
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Fully digestible amylopectin corn starch; 70g high-amylose maize starch
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: dietary supplementation
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention