<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03028831</url>
  </required_header>
  <id_info>
    <org_study_id>PRO16080079</org_study_id>
    <nct_id>NCT03028831</nct_id>
  </id_info>
  <brief_title>Fiber to Reduce Colon Cancer in Alaska Native People</brief_title>
  <official_title>Randomized Controlled Trial of Resistant Starch to Reduce Colon Cancer Risk in Alaska Native People.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pittsburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Alaska Native Tribal Health Consortium</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Alaska native people (AN) have the highest recorded incidence and death rate from colon&#xD;
      cancer in the world (&gt;90:100,000). We hypothesize that the AN, despite their high consumption&#xD;
      of anti-inflammatory and antineoplastic n-3 fish oils, are at increased risk of colon cancer&#xD;
      because of colonic butyrate deficiency resulting from their remarkably low consumption of&#xD;
      fiber-containing foods. We hypothesize that fiber supplementation of their usual diet will&#xD;
      result in a bloom of butyrate producing microbes in the colon, resulting in increased&#xD;
      butyrate production, which will suppress their high microbial secondary bile acid production,&#xD;
      antagonize the actions of other food (smoked fish) and environmental carcinogens (tobacco,&#xD;
      alcohol), and interact with the high circulating levels of n-3 fish oils to suppress colonic&#xD;
      inflammation and cancer risk. In order to investigate this, we will conduct a randomized&#xD;
      double-blinded 4-week clinical trial in up to 100 randomizable healthy, middle-aged AN&#xD;
      undergoing screening colonoscopy, with the objective of obtaining 60 completed interventions.&#xD;
      The interventions will consist of either a high-dose soluble fiber supplement given as a&#xD;
      drink, together with their usual diet which currently contains about 15g total fiber/d, or to&#xD;
      a control digestible starch drink plus their usual diet. The primary endpoint will be a&#xD;
      clinically significant reduction in Ki67 proliferative colonic mucosal biomarkers of cancer&#xD;
      risk. Microbiome and metabolome mechanisms responsible for the anticipated changes in mucosal&#xD;
      biomarkers will also be investigated. Our results in extreme risk AN will be further&#xD;
      evaluated by comparison to similar measurements previously made in minimal risk rural&#xD;
      Africans and intermediate risk African Americans. Our results will be used to provide the&#xD;
      scientific basis for a definitive large-scale high-fiber supplementation study (to achieve&#xD;
      &gt;50g total fiber/d) to suppress adenomatous polyp recurrence following colonoscopy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Randomization for the double blind, placebo controlled, clinical trial: Recruitment will&#xD;
      continue until 60 volunteers have completed the intervention study. Based on previous&#xD;
      experience with similar studies, we anticipate 20% of screened patients to be ineligible or&#xD;
      drop out, which means, so we plan on consenting and screening approximately 100 potential&#xD;
      participants. Baseline data from these participants will be retained. Individuals will be&#xD;
      randomized via minimisation (based on age, sex, polypectomy, high fish consumption, and BMI -&#xD;
      factors that might influence microbiota composition and function)) to either the resistant&#xD;
      starch (RS) group or the control digestible starch (DS) group upon completion of the&#xD;
      Stabilization Period.&#xD;
&#xD;
        1. RS Group: Participants will continue with their usual diet plus fiber supplement given&#xD;
           as a daily dose of 70g high-amylose maize starch (HAM-RS, HI-MAIZE®260: Ingredion&#xD;
           Incorporated, Bridgewater, NJ), which contains 42g of type 2 resistant starch, for 4&#xD;
           weeks. Data from previous studies[69] suggests that their usual diet will contain&#xD;
           approximately 13g dietary fiber/day, chiefly insoluble, indicating that total fiber&#xD;
           intake would be approx. 55g/d. Supplements will be pre-weighed out in batches from the&#xD;
           same source and kept in airtight containers. The supplement may be taken as a single or&#xD;
           divided dose dissolved in 250ml water, low fat milk, or orange juice&#xD;
&#xD;
        2. DS (Control) Group participants will continue on their usual diet, plus 70g of fully&#xD;
           digestible starch (waxy corn starch comprised of amylopectin, AMIOCA® corn starch,&#xD;
           Ingredion Incorporated, Bridgewater, NJ ) weighed out, analyzed, and prepared as&#xD;
           previously. The RS and control supplements will appear and taste similar, allowing for&#xD;
           coding and distribution in a double-blind fashion. The supplements will be equicaloric.&#xD;
&#xD;
      Interventions will include fecal and colonic content sampling for measurement of the&#xD;
      microbiome and metabolome, and flexible sigmoidoscopy to obtain mucosal biopsies before and&#xD;
      after the dietary supplementation.&#xD;
&#xD;
      Monitoring During the Clinical Trial: This will follow the scheme laid out on Figure 7. On&#xD;
      day 0, participants will visit the clinic and will be asked to save their first fecal sample&#xD;
      using our standard operating procedure developed and proven to be effective in our last&#xD;
      study. They will then be given their first supplement drink made up in their vehicle of&#xD;
      choice, and taken with a standard meal provided by the diet kitchen. During the trial, they&#xD;
      will be instructed on the use of a simple diary to be completed at home. This will record the&#xD;
      major food items consumed each day, the timing and completion of drink supplements, as well&#xD;
      as the bowel function questionnaire to assess daily GI tolerance, i.e. abdominal discomfort,&#xD;
      distension, gas, bowel frequency, nausea, vomiting. They will be asked to return to the&#xD;
      clinic for a follow-up appointment on day 7, 14 and 21 in order to repeat the fecal and&#xD;
      breath tests described above. At the same time, body weight will be monitored using one&#xD;
      scale. At the end of 4 weeks, participants will be asked to return to the clinic for repeat&#xD;
      of the colonic sampling performed at baseline.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 11, 2017</start_date>
  <completion_date type="Actual">December 31, 2022</completion_date>
  <primary_completion_date type="Actual">December 31, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>dietary supplementation</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>similar packets, similar appearing supplements</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>colonic mucosal proliferation</measure>
    <time_frame>4 weeks</time_frame>
    <description>biomarker of cancer risk</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>colonic microbiota</measure>
    <time_frame>4 weeks</time_frame>
    <description>fecal and colonic microbiota analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>colonic secondary bile acids</measure>
    <time_frame>4 weeks</time_frame>
    <description>fecal and colonic conjugated bile acid analysis</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Colon Cancer</condition>
  <arm_group>
    <arm_group_label>Resistant Starch</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>70g high-amylose maize starch which contains 42g of type 2 resistant starch</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Digestible Starch</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>70g of fully digestible starch comprised of amylopectin corn starch.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>70g of fully digestible starch amylopectin corn starch</intervention_name>
    <description>Fully digestible amylopectin corn starch</description>
    <arm_group_label>Digestible Starch</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Resistant starch</intervention_name>
    <description>70g high-amylose maize starch</description>
    <arm_group_label>Resistant Starch</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: Healthy AN volunteers (from GI standpoint) between 40-70 years (age at&#xD;
        which colon cancer screening colonoscopy is recommended in this population) and BMI between&#xD;
        18-40 Kg/m2. It should be noted that in our previous study, we found no difference in the&#xD;
        responses of the key parameters (mucosal biomarkers, butyrate and secondary bile acid&#xD;
        producers, fecal SCFA and bile acids) to increased fiber diets between those with normal&#xD;
        body weight, those overweight, and those who were obese (Nature Comm Supplement). Patients&#xD;
        who have, or have had noncancerous polyps removed previously by colonoscopy will be&#xD;
        eligible. Alaska Native race will be defined as those eligible to receive health care&#xD;
        through the Alaska Tribal Health System. Exclusion criteria: These are detailed under Human&#xD;
        Subjects. Participants will be ineligible if they have a history of familial adenomatous&#xD;
        polyposis or hereditary non-polyposis colorectal cancer, or have previous colonoscopic&#xD;
        evidence of inflammatory bowel disease or colon cancer. Also ineligible will be individuals&#xD;
        with known renal, hepatic, or bleeding disorders; previous GI surgery resulting in&#xD;
        disturbed gut function due to of loss of bowel or altered anatomy; or any form of chronic&#xD;
        GI disease resulting in disturbed gut function, diarrhea, and malabsorption. Individuals&#xD;
        with antibiotic use within the past 12 weeks, current steroids use, or on medical treatment&#xD;
        for diabetes, will also be excluded.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gabriela Riscuta</last_name>
    <role>Study Director</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Alaskan Native Tribal Health Consortium</name>
      <address>
        <city>Anchorage</city>
        <state>Alaska</state>
        <zip>99508</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Upittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>O'Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 2016 Dec;13(12):691-706. doi: 10.1038/nrgastro.2016.165. Epub 2016 Nov 16.</citation>
    <PMID>27848961</PMID>
  </reference>
  <results_reference>
    <citation>O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM, Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S, Puylaert PG, DeLany J, Krasinskas A, Benefiel AC, Kaseb HO, Newton K, Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015 Apr 28;6:6342. doi: 10.1038/ncomms7342.</citation>
    <PMID>25919227</PMID>
  </results_reference>
  <results_reference>
    <citation>Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR, O'Keefe SJ. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013 Jul;98(1):111-20. doi: 10.3945/ajcn.112.056689. Epub 2013 May 29.</citation>
    <PMID>23719549</PMID>
  </results_reference>
  <results_reference>
    <citation>Koller KR, Wilson A, Normolle DP, Nicholson JK, Li JV, Kinross J, Lee FR, Flanagan CA, Merculieff ZT, Iyer P, Lammers DL, Thomas TK, O'Keefe SJD. Dietary fibre to reduce colon cancer risk in Alaska Native people: the Alaska FIRST randomised clinical trial protocol. BMJ Open. 2021 Aug 27;11(8):e047162. doi: 10.1136/bmjopen-2020-047162.</citation>
    <PMID>34452959</PMID>
  </results_reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>January 18, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 23, 2017</study_first_posted>
  <last_update_submitted>May 13, 2023</last_update_submitted>
  <last_update_submitted_qc>May 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Stephen O'Keefe</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>we will use a public deposit when all the data analysis is completed</ipd_description>
    <ipd_time_frame>2012</ipd_time_frame>
    <ipd_access_criteria>public</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03028831
org study id: PRO16080079
nct id: NCT03028831
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: dietary supplementation
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: similar packets, similar appearing supplements
measure: colonic mucosal proliferation
time frame: 4 weeks
description: biomarker of cancer risk
measure: colonic microbiota
time frame: 4 weeks
description: fecal and colonic microbiota analysis
measure: colonic secondary bile acids
time frame: 4 weeks
description: fecal and colonic conjugated bile acid analysis
arm group label: Resistant Starch
arm group type: Active Comparator
description: 70g high-amylose maize starch which contains 42g of type 2 resistant starch
arm group label: Digestible Starch
arm group type: Placebo Comparator
description: 70g of fully digestible starch comprised of amylopectin corn starch.
intervention type: Dietary Supplement
intervention name: 70g of fully digestible starch amylopectin corn starch
description: Fully digestible amylopectin corn starch
arm group label: Digestible Starch
intervention type: Dietary Supplement
intervention name: Resistant starch
description: 70g high-amylose maize starch
arm group label: Resistant Starch
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Gabriela Riscuta
role: Study Director
affiliation: National Cancer Institute (NCI)
facility: 
facility: 
country: United States
citation: O'Keefe SJ. Diet, microorganisms and their metabolites, and colon cancer. Nat Rev Gastroenterol Hepatol. 2016 Dec;13(12):691-706. doi: 10.1038/nrgastro.2016.165. Epub 2016 Nov 16.
PMID: 27848961
citation: O'Keefe SJ, Li JV, Lahti L, Ou J, Carbonero F, Mohammed K, Posma JM, Kinross J, Wahl E, Ruder E, Vipperla K, Naidoo V, Mtshali L, Tims S, Puylaert PG, DeLany J, Krasinskas A, Benefiel AC, Kaseb HO, Newton K, Nicholson JK, de Vos WM, Gaskins HR, Zoetendal EG. Fat, fibre and cancer risk in African Americans and rural Africans. Nat Commun. 2015 Apr 28;6:6342. doi: 10.1038/ncomms7342.
PMID: 25919227
citation: Ou J, Carbonero F, Zoetendal EG, DeLany JP, Wang M, Newton K, Gaskins HR, O'Keefe SJ. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr. 2013 Jul;98(1):111-20. doi: 10.3945/ajcn.112.056689. Epub 2013 May 29.
PMID: 23719549
citation: Koller KR, Wilson A, Normolle DP, Nicholson JK, Li JV, Kinross J, Lee FR, Flanagan CA, Merculieff ZT, Iyer P, Lammers DL, Thomas TK, O'Keefe SJD. Dietary fibre to reduce colon cancer risk in Alaska Native people: the Alaska FIRST randomised clinical trial protocol. BMJ Open. 2021 Aug 27;11(8):e047162. doi: 10.1136/bmjopen-2020-047162.
PMID: 34452959
responsible party type: Principal Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Stephen O'Keefe
investigator title: MD
mesh term: Colonic Neoplasms
sharing ipd: Yes
ipd description: we will use a public deposit when all the data analysis is completed
ipd time frame: 2012
ipd access criteria: public