<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/NCT01661764</url>
  </required_header>
  <id_info>
    <org_study_id>11165</org_study_id>
    <secondary_id>R01CA160938</secondary_id>
    <nct_id>NCT01661764</nct_id>
  </id_info>
  <brief_title>Fish Oil Supplementation, Nutrigenomics and Colorectal Cancer Prevention</brief_title>
  <official_title>Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Prevention</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Colorectal cancer is the second leading cause of cancer-related death within the United&#xD;
      States. Animal models and observational studies have suggested that marine-derived n-3&#xD;
      polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid&#xD;
      [DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative&#xD;
      proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils.&#xD;
      This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the&#xD;
      cyclo-oxygenase (COX) pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid&#xD;
      overproduced in colorectal neoplasms while EPA is converted to the anti-inflammatory&#xD;
      prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be altered through dietary&#xD;
      changes, genetic factors may also influence this ratio. Recent genetic studies have&#xD;
      demonstrated that much of the tissue levels of ARA is determined by differences in a gene&#xD;
      called fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion&#xD;
      of linoleic acid, the most commonly consumed PUFA in the Western diet, to ARA, and one&#xD;
      particular genetic variant caller rs174537 is associated with lower fatty acid desaturase&#xD;
      activity and subsequently lower tissue levels of ARA.&#xD;
&#xD;
      The study hypothesis is that individuals with genetically determined lower activity of FADS1&#xD;
      will derive greater benefit from fish oil supplementation than individuals with higher FADS1&#xD;
      activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3&#xD;
      PUFA ratio. To test this hypothesis the investigators will recruit 150 participants with&#xD;
      recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial&#xD;
      randomized controlled trial. The first factor will be FADS1 genotype (GG, GT, and TT) and the&#xD;
      second factor will be fish oil supplementation (fish oil versus placebo). The primary outcome&#xD;
      will be the change in rectal epithelial cell growth and cell death. Secondary outcomes will&#xD;
      include rectal epithelial cell expression of genes important in PGE2 production, rectal cell&#xD;
      production of PGE2 and PGE3, rectal mucosal tissue levels of fatty acids, and changes in&#xD;
      biomarkers of inflammation (C-reactive protein), adipokines (leptin, adiponectin), and&#xD;
      markers of insulin sensitivity.&#xD;
&#xD;
      The specific aims include: 1) to determine the efficacy of fish oil supplements on rectal&#xD;
      epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to&#xD;
      determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil&#xD;
      supplementation for colorectal cancer chemoprevention. The investigators long-term objectives&#xD;
      are to determine genetic factors that might influence the efficacy of fish oil&#xD;
      supplementation in order to conduct a more definitive adenoma recurrence trial using&#xD;
      marine-derived n-3 PUFAs. The investigators anticipate that fish oil will have&#xD;
      anti-neoplastic effect and individuals with low FADS1 activity will have a greater response&#xD;
      compared to individuals with high FADS1 activity&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1.Rationale and Specific Aims&#xD;
&#xD;
      Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of&#xD;
      cancer related mortality in the United States. Animal and human studies have suggested that&#xD;
      the marine-derived n-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and&#xD;
      docosahexanoic acid (DHA), have cancer inhibitory properties while conversely, n-6 PUFAs such&#xD;
      as arachidonic acid (ARA) may promote tumorigenesis. The mechanism behind these opposing&#xD;
      effects is likely due to differences in the biological activity of their eicosanoids end&#xD;
      products and their effects on chronic inflammation. Prostaglandin E2 (PGE2) is a&#xD;
      pro-inflammatory eicosanoid that is aberrantly produced in both colorectal adenomas and&#xD;
      cancer and is derived from ARA via the cyclo-oxygenase pathway. EPA is converted through the&#xD;
      same pathway into prostaglandin E3, which has 4 to 7- fold less prostaglandin E receptor&#xD;
      affinity, is less inflammatory, and may even be pro-apoptotic compared to PGE2. As such, it&#xD;
      may be the ratio of ARA to EPA and DHA rather than the absolute levels of marine-derived n-3&#xD;
      PUFAs that contribute most towards their antiproliferative and pro-apoptotic effects.&#xD;
&#xD;
      The ratio of ARA to EPA + DHA can be manipulated through fish oil supplementation, however;&#xD;
      genetic factors may play a key role on determining this ratio. Recent genome-wide association&#xD;
      and haplotype studies have demonstrated that up to 28% of the additive variance in tissue&#xD;
      levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1).&#xD;
      FADS1 is the rate-limiting enzyme in the conversion of linoleic acid (LA), the most commonly&#xD;
      consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap&#xD;
      -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue&#xD;
      levels of ARA. While EPA can be produced in vivo from α-linolenic acid, in humans, this&#xD;
      process is extremely inefficient and most tissue level EPA derives directly from dietary&#xD;
      consumption of fatty fish. Thus, high activity of FAD1 and subsequently increased tissue&#xD;
      levels of ARA may offset some of the potential benefits of dietary supplementation with fish&#xD;
      oil. To date, no previously published studies have investigated how genetic variants that&#xD;
      influence fatty acid desaturase activity might modify the beneficial effects of fish oil&#xD;
      supplementation.&#xD;
&#xD;
      The investigators hypothesis is that the individuals with genetically determined lower&#xD;
      activity of FADS1 will derive greater benefit from fish oil supplementation than individuals&#xD;
      with higher FADS1 activity because of lower tissue levels of ARA and subsequently a more&#xD;
      favorable ARA to EPA + DHA ratio. To test this hypothesis the investigators will recruit 150&#xD;
      participants with recently identified adenomatous polyps and conduct a 6-month double blind 3&#xD;
      X 2 factorial randomized controlled trial. The first factor will be the rs174537 genotype&#xD;
      (GG, GT, and TT) in the FADS1 gene and the second factor will be fish oil supplementation&#xD;
      (fish oil versus placebo). The primary study outcome will be the change from baseline in&#xD;
      rectal epithelial cell proliferation as measured by Ki-67 labeling and rectal crypt apoptosis&#xD;
      as measured by TUNEL. Secondary endpoints will include rectal epithelial cell expression of&#xD;
      COX-2 and 15-PGDH, rectal cell production of PGE2 and PGE3, rectal cell fatty acid&#xD;
      concentrations, as well as, changes from baseline in biomarkers of inflammation (C-reactive&#xD;
      protein), adipokines (leptin, adiponectin), and markers of insulin sensitivity (HOMA-IR).&#xD;
&#xD;
      The Specific Aims for this research proposal are:&#xD;
&#xD;
        1. to determine the efficacy of fish oil supplements on rectal epithelial cell&#xD;
           proliferation indexes and markers of rectal crypt apoptosis; and,&#xD;
&#xD;
        2. to determine the effect of genetically determined fatty acid desaturase activity on fish&#xD;
           oil supplementation for markers of colorectal cancer risk.&#xD;
&#xD;
      The investigators long-term objectives are to determine genetic factors that might influence&#xD;
      the efficacy of fish oil supplementation in order to conduct a more definitive adenoma&#xD;
      recurrence trial using marine-derived n-3 PUFAs. The investigators anticipate that fish oil&#xD;
      will have anti-neoplastic effect and individuals with low FADS1 activity will have a greater&#xD;
      response compared to individuals with high FADS1 activity. This study will be the first to&#xD;
      investigate the nutrigenomics of fish oil supplementation in colorectal cancer&#xD;
      chemoprevention and may have implications beyond cancer prevention as fish oil is being&#xD;
      actively investigated for its anti-inflammatory effects in cardiovascular and psychiatric&#xD;
      diseases as well as diabetes mellitus and the metabolic syndrome.&#xD;
&#xD;
      2. Recruitment and Retention&#xD;
&#xD;
      The investigators will identify eligible participants based on the inclusion criteria by&#xD;
      reviewing study data and medical record data collected in the Tennessee Colorectal Polyp&#xD;
      Study(TCPS). Participants still eligible after record review will be mailed an introductory&#xD;
      letter inviting them to participate. One week after the letter is mailed; a trained&#xD;
      interviewer from the Vanderbilt Survey Research Shared Resource (SRSR) will call the&#xD;
      potential participants to provide more detailed information about the study, answer questions&#xD;
      about the study, and to see if they may be interested in participating. At that time, an&#xD;
      appointment will be made with the participant for the baseline in-person visit. After the&#xD;
      initial visit and informed consent is obtained an interviewer from the SRSR will conduct the&#xD;
      baseline interview survey and 24-hour dietary recalls. At the baseline visit, the&#xD;
      investigators will re-genotype rs174535 to confirm the accuracy of the imputation process.&#xD;
      This strategy will allow the investigators to efficiently and accurately identify appropriate&#xD;
      candidates for our study.&#xD;
&#xD;
      Eligible subjects will present to the Vanderbilt General Clinical Research Center (GCRC) for&#xD;
      the initial visit and baseline study procedures. Participants who are eligible for the study&#xD;
      and provide written consent for enrollment will have blood obtained; an adipose tissue biopsy&#xD;
      performed, and undergoes the baseline rectal mucosal biopsy procedure. Treatment assignment&#xD;
      will be obtained from the Vanderbilt Investigational Pharmacy by a coordinator. The first&#xD;
      dose of the study medication will be given to patients at the initial visit and the date and&#xD;
      time recorded. This date and time will be considered the time of randomization.&#xD;
&#xD;
      3. Randomization&#xD;
&#xD;
      Randomization will be performed according to a permuted block randomization scheme stratified&#xD;
      on the three genotypes. Randomization will proceed within these three strata with a block&#xD;
      size of balancing interval, varying randomly according to the outcome of a computer generated&#xD;
      random number. This ensures that the cumulative proportion of assignments to each treatment&#xD;
      will be balanced after each block of assignments has been made.&#xD;
&#xD;
      4. Study Procedures&#xD;
&#xD;
        1. Data Collection&#xD;
&#xD;
           Because outside dietary exposure to both n-6 and n-3 PUFAs could possibly confound the&#xD;
           effect of fish oil supplementation the investigators will perform a total of four&#xD;
           24-hour dietary recall studies for each participant over the course of the study. At&#xD;
           enrollment, the investigators will conduct two 24-hour dietary assessments, one on the&#xD;
           weekday and one on the weekend, as participants' diet may differ based on the day of the&#xD;
           week. In addition the investigators will conduct one 24-hour dietary recall at week 8&#xD;
           and at week 16. The investigators will use data collected from these 24-hour dietary&#xD;
           assessments along with standard food composition tables to calculate dietary exposure to&#xD;
           PUFAs.&#xD;
&#xD;
           The investigators will determine adherence to study drug at each in-person visit during&#xD;
           the study. Medication and medication changes will be recorded at these visits. Patients&#xD;
           who initiate a new NSAID during the study will be withdrawn and an exit visit performed.&#xD;
           Adherence to fish oil will also be determined through RBC phospholipid membrane fatty&#xD;
           acid analysis performed at month 3 and month 6. In addition, to determine whether fish&#xD;
           oil supplementation also influences fatty acid membrane concentration at the target&#xD;
           tissue, the investigators will determine the change in rectal epithelial cell&#xD;
           phospholipid membrane fatty acid concentration.&#xD;
&#xD;
        2. Fish oil Capsules&#xD;
&#xD;
           Participants allocated to fish oil supplementation will be instructed to take three&#xD;
           Lovaza® capsules each containing 465 mg of EPA and 375 mg DHA daily; this will provide a&#xD;
           total daily dose of 1395 mg EPA plus 1125 mg DHA for a total daily dose of fish oil of&#xD;
           2.5 grams. Patients will take one tablet three times a day with meals. Lovaza® capsules&#xD;
           are the only FDA approved preparation of fish oil, and as such, the quality of the drug&#xD;
           is monitored and assured. Pharmacological grade fish oil capsules have the advantage of&#xD;
           providing high concentrations of PUFAs, low levels of contaminants, such as mercury, and&#xD;
           almost no fish odor.&#xD;
&#xD;
        3. Placebo Capsules&#xD;
&#xD;
           The investigators will use oleic acid as a placebo. The reason for the use of oleic acid&#xD;
           is several-fold. First, oleic acid (olive oil) capsules have a similar texture, size,&#xD;
           color, and consistency to fish oil capsules. More importantly, oleic acid does not&#xD;
           undergo conversion to an eicosanoid or any other metabolically active product. This is&#xD;
           opposed to corn oil, which has also been used as a placebo in fish oil studies but is&#xD;
           primarily linoleic acid and could subsequently increase tissue levels of ARA and&#xD;
           confound the results of our study. Oleic acid has been used as a placebo in several&#xD;
           prior studies of fish oil supplementation and is well tolerated.&#xD;
&#xD;
        4. Assessment Visits&#xD;
&#xD;
      Patients will attend the GCRC clinic at the baseline (initial visit), after 3 months of study&#xD;
      treatment (mid-point visit), and after 6 months of study treatment (end visit). The study&#xD;
      coordinator will contact participants every 4 weeks over the course of the study to encourage&#xD;
      adherence to the study protocol. At the 3-month and 6-month visits, compliance with treatment&#xD;
      will be monitored by capsule count and measurement of RBC phospholipid fatty acid&#xD;
      concentrations. Adverse events will be recorded at these visits.&#xD;
&#xD;
      5. Data management and quality control&#xD;
&#xD;
      The Vanderbilt GCRC Informatics Core will be used as a central location for data processing&#xD;
      and analysis. Vanderbilt University has developed software tools and workflow methodology for&#xD;
      electronic collection and management of research study data. (132) REDCap (Research&#xD;
      Electronic Data Capture) is a secure, web-based application that provides an intuitive&#xD;
      interface for users to enter validated data remotely (with automated data type and range&#xD;
      checks), data manipulation audit trails and reporting, and an export mechanism for&#xD;
      end-of-study export of data to common statistical packages.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 4, 2013</start_date>
  <completion_date type="Actual">January 23, 2018</completion_date>
  <primary_completion_date type="Actual">December 26, 2016</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rectal Epithelial Cell Proliferation</measure>
    <time_frame>6 month</time_frame>
    <description>The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rectal Epithelial Cell Apoptosis</measure>
    <time_frame>6 months</time_frame>
    <description>The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&amp;E stained sections.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rectal Epithelial Cell COX-2 Expression</measure>
    <time_frame>6 months</time_frame>
    <description>Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rectal Epithelial Cell 15-PGDH Expression</measure>
    <time_frame>6 months</time_frame>
    <description>Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rectal Epithelial Cell Phospholipid Fatty Acid Content</measure>
    <time_frame>6 months</time_frame>
    <description>Lipids will be extracted using the method of Folch-Lees</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rectal Epithelial Cell Production of PGE2 and PGE3</measure>
    <time_frame>6 months</time_frame>
    <description>liquid chromatography/tandem mass spectrometric on rectal biopsy samples</description>
  </secondary_outcome>
  <other_outcome>
    <measure>C-reactive Protein</measure>
    <time_frame>6 months</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Adipokines</measure>
    <time_frame>6 months</time_frame>
    <description>leptin and adiponectin</description>
  </other_outcome>
  <other_outcome>
    <measure>Insulin Sensitivity</measure>
    <time_frame>6 months</time_frame>
    <description>homeostasis model assessment-insulin resistance (HOMA-IR) HOMA-IR. Fasting insulin and glucose were be used to determine HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (µU/ml)]/22.5]&quot;, Optimal insulin sensitivity: &lt; 1, Early insulin resistance: &gt; 1.9, Significant insulin resistance: &gt; 2.9</description>
  </other_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">141</enrollment>
  <condition>Colorectal Adenomatous Polyps</condition>
  <arm_group>
    <arm_group_label>rs174535 (GG), fish oil supplements</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Eicosapentanoic acid and docosahexanoic acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rs174535 (GG), placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oleic Acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rs174535 (GT), fish oil supplements</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Eicosapentanoic acid and docosahexanoic acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rs174535 (GT), placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oleic Acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rs174535 (TT), fish oil supplement</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Eicosapentanoic acid and docosahexanoic acid</description>
  </arm_group>
  <arm_group>
    <arm_group_label>rs174535 (TT), placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Oleic Acid</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Eicosapentanoic acid and docosahexanoic acid</intervention_name>
    <description>1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
    <arm_group_label>rs174535 (GG), fish oil supplements</arm_group_label>
    <arm_group_label>rs174535 (GT), fish oil supplements</arm_group_label>
    <arm_group_label>rs174535 (TT), fish oil supplement</arm_group_label>
    <other_name>Lovaza</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oleic Acid</intervention_name>
    <description>Placebo</description>
    <arm_group_label>rs174535 (GG), placebo</arm_group_label>
    <arm_group_label>rs174535 (GT), placebo</arm_group_label>
    <arm_group_label>rs174535 (TT), placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 40 and &lt; 80 years of age&#xD;
&#xD;
          -  History of 1 or more adenomatous polyps&#xD;
&#xD;
          -  Consent to be contacted for future studies&#xD;
&#xD;
          -  Participants with known genotype for rs174535 in FADS1&#xD;
&#xD;
          -  Prior participation in the Tennessee Colorectal Polyp Study or the Personalized&#xD;
             Prevention of Colorectal Cancer Trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previously resected colorectal cancer&#xD;
&#xD;
          -  Coronary artery disease or congestive heart failure&#xD;
&#xD;
          -  Current metabolic or life-threatening disease&#xD;
&#xD;
          -  Currently taking fish oil supplements&#xD;
&#xD;
          -  Inability or unwillingness to stop NSAIDs or ASA during the study&#xD;
&#xD;
          -  Allergic to fish products&#xD;
&#xD;
          -  Diagnosis of inflammatory bowel disease&#xD;
&#xD;
          -  Diagnosis of any cancer (except non-melanoma skin cancer)&#xD;
&#xD;
          -  Diagnosis of liver or kidney disease&#xD;
&#xD;
          -  Pregnant or breast feeding&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Harvey J Murff, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <results_first_submitted>January 23, 2018</results_first_submitted>
  <results_first_submitted_qc>April 5, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">May 8, 2018</results_first_posted>
  <last_update_submitted>May 11, 2018</last_update_submitted>
  <last_update_submitted_qc>May 11, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University</investigator_affiliation>
    <investigator_full_name>Harvey Murff</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Colorectal Neoplasm</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenomatous Polyps</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 4, 2012</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/64/NCT01661764/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>rs174535 (GG), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="P2">
          <title>rs174535 (GG), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="P3">
          <title>rs174535 (GT), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="P4">
          <title>rs174535 (GT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="P5">
          <title>rs174535 (TT), Fish Oil Supplement</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="P6">
          <title>rs174535 (TT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="26"/>
                <participants group_id="P2" count="25"/>
                <participants group_id="P3" count="25"/>
                <participants group_id="P4" count="26"/>
                <participants group_id="P5" count="19"/>
                <participants group_id="P6" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="20"/>
                <participants group_id="P3" count="22"/>
                <participants group_id="P4" count="24"/>
                <participants group_id="P5" count="16"/>
                <participants group_id="P6" count="18"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="3"/>
                <participants group_id="P6" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>rs174535 (GG), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="B2">
          <title>rs174535 (GG), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="B3">
          <title>rs174535 (GT), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="B4">
          <title>rs174535 (GT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="B5">
          <title>rs174535 (TT), Fish Oil Supplement</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="B6">
          <title>rs174535 (TT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="B7">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="26"/>
            <count group_id="B2" value="25"/>
            <count group_id="B3" value="25"/>
            <count group_id="B4" value="26"/>
            <count group_id="B5" value="19"/>
            <count group_id="B6" value="20"/>
            <count group_id="B7" value="141"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58.0" spread="6.7"/>
                    <measurement group_id="B2" value="60" spread="8.3"/>
                    <measurement group_id="B3" value="59.6" spread="9.6"/>
                    <measurement group_id="B4" value="58.9" spread="7.4"/>
                    <measurement group_id="B5" value="60.5" spread="9.8"/>
                    <measurement group_id="B6" value="61.6" spread="7.6"/>
                    <measurement group_id="B7" value="59.6" spread="8.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="8"/>
                    <measurement group_id="B7" value="68"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="18"/>
                    <measurement group_id="B4" value="14"/>
                    <measurement group_id="B5" value="11"/>
                    <measurement group_id="B6" value="12"/>
                    <measurement group_id="B7" value="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rectal Epithelial Cell Proliferation</title>
        <description>The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
        <time_frame>6 month</time_frame>
        <population>Patients with before and after rectal biopsies</population>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell Proliferation</title>
          <description>The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
          <population>Patients with before and after rectal biopsies</population>
          <units>percentage of cells positive</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.3" spread="6.8"/>
                    <measurement group_id="O2" value="20.3" spread="7.6"/>
                    <measurement group_id="O3" value="18.9" spread="8.5"/>
                    <measurement group_id="O4" value="16.8" spread="6.2"/>
                    <measurement group_id="O5" value="15.7" spread="5.4"/>
                    <measurement group_id="O6" value="20.8" spread="6.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Rectal Epithelial Cell Apoptosis</title>
        <description>The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&amp;E stained sections.</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell Apoptosis</title>
          <description>The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&amp;E stained sections.</description>
          <units>percentage of cells positive</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.17" spread="1.79"/>
                    <measurement group_id="O2" value="1.30" spread="1.30"/>
                    <measurement group_id="O3" value="1.00" spread="1.27"/>
                    <measurement group_id="O4" value="2.61" spread="4.55"/>
                    <measurement group_id="O5" value="1.44" spread="1.77"/>
                    <measurement group_id="O6" value="1.33" spread="1.78"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rectal Epithelial Cell COX-2 Expression</title>
        <description>Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell COX-2 Expression</title>
          <description>Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
          <units>percentage of cells positive</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.47" spread="4.40"/>
                    <measurement group_id="O2" value="4.62" spread="2.81"/>
                    <measurement group_id="O3" value="5.10" spread="3.05"/>
                    <measurement group_id="O4" value="5.31" spread="3.32"/>
                    <measurement group_id="O5" value="2.86" spread="1.40"/>
                    <measurement group_id="O6" value="5.86" spread="4.29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rectal Epithelial Cell 15-PGDH Expression</title>
        <description>Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell 15-PGDH Expression</title>
          <description>Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).</description>
          <units>percentage of cells positive</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.5" spread="8.14"/>
                    <measurement group_id="O2" value="27.6" spread="4.58"/>
                    <measurement group_id="O3" value="25.1" spread="6.42"/>
                    <measurement group_id="O4" value="29.3" spread="6.3"/>
                    <measurement group_id="O5" value="23.8" spread="8.5"/>
                    <measurement group_id="O6" value="27.1" spread="6.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rectal Epithelial Cell Phospholipid Fatty Acid Content</title>
        <description>Lipids will be extracted using the method of Folch-Lees</description>
        <time_frame>6 months</time_frame>
        <population>Due to inadequate rectal tissue specimens we were unable to measure rectal tissue phospholipids</population>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell Phospholipid Fatty Acid Content</title>
          <description>Lipids will be extracted using the method of Folch-Lees</description>
          <population>Due to inadequate rectal tissue specimens we were unable to measure rectal tissue phospholipids</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rectal Epithelial Cell Production of PGE2 and PGE3</title>
        <description>liquid chromatography/tandem mass spectrometric on rectal biopsy samples</description>
        <time_frame>6 months</time_frame>
        <population>For some participants the volume of frozen tissue was not enough to measure rectal eicosanoids and are not included in the analysis (2 from GG, fish oil, 2 from GG, placebo, 3 from GT fish oil, 4 GT placebo, 1 TT fish oil and 3 TT placebo)</population>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Rectal Epithelial Cell Production of PGE2 and PGE3</title>
          <description>liquid chromatography/tandem mass spectrometric on rectal biopsy samples</description>
          <population>For some participants the volume of frozen tissue was not enough to measure rectal eicosanoids and are not included in the analysis (2 from GG, fish oil, 2 from GG, placebo, 3 from GT fish oil, 4 GT placebo, 1 TT fish oil and 3 TT placebo)</population>
          <units>ng/g</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
                <count group_id="O2" value="18"/>
                <count group_id="O3" value="19"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="15"/>
                <count group_id="O6" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>PGE2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.4" spread="13.3"/>
                    <measurement group_id="O2" value="23.6" spread="33.4"/>
                    <measurement group_id="O3" value="14.4" spread="19.7"/>
                    <measurement group_id="O4" value="22.1" spread="40.0"/>
                    <measurement group_id="O5" value="16.6" spread="14.1"/>
                    <measurement group_id="O6" value="24.4" spread="27.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>PGE3</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.40" spread="1.87"/>
                    <measurement group_id="O2" value="2.89" spread="3.38"/>
                    <measurement group_id="O3" value="2.10" spread="2.00"/>
                    <measurement group_id="O4" value="2.63" spread="2.98"/>
                    <measurement group_id="O5" value="4.43" spread="9.04"/>
                    <measurement group_id="O6" value="1.84" spread="2.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>C-reactive Protein</title>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>C-reactive Protein</title>
          <units>mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.98" spread="6.64"/>
                    <measurement group_id="O2" value="3.87" spread="7.13"/>
                    <measurement group_id="O3" value="2.11" spread="2.23"/>
                    <measurement group_id="O4" value="4.96" spread="6.92"/>
                    <measurement group_id="O5" value="2.58" spread="4.00"/>
                    <measurement group_id="O6" value="2.34" spread="2.85"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Adipokines</title>
        <description>leptin and adiponectin</description>
        <time_frame>6 months</time_frame>
        <population>Adipokines were not measured on all trial participants due to assay expense. Samples measurements were not completed on 3 GG, fish oil, 0 GG, placebo, 3 GT fish oil, 4 GT placebo, 7 TT fish oil, 9 TT placebo</population>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Adipokines</title>
          <description>leptin and adiponectin</description>
          <population>Adipokines were not measured on all trial participants due to assay expense. Samples measurements were not completed on 3 GG, fish oil, 0 GG, placebo, 3 GT fish oil, 4 GT placebo, 7 TT fish oil, 9 TT placebo</population>
          <units>ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="19"/>
                <count group_id="O4" value="20"/>
                <count group_id="O5" value="9"/>
                <count group_id="O6" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Leptin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25.3" spread="19.0"/>
                    <measurement group_id="O2" value="24.0" spread="30.1"/>
                    <measurement group_id="O3" value="20.2" spread="15.7"/>
                    <measurement group_id="O4" value="27.9" spread="22.0"/>
                    <measurement group_id="O5" value="10.9" spread="8.62"/>
                    <measurement group_id="O6" value="23.0" spread="26.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Adiponectin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.4" spread="25.8"/>
                    <measurement group_id="O2" value="20.5" spread="17.9"/>
                    <measurement group_id="O3" value="18.9" spread="13.4"/>
                    <measurement group_id="O4" value="14.9" spread="13.9"/>
                    <measurement group_id="O5" value="29.4" spread="33.9"/>
                    <measurement group_id="O6" value="15.3" spread="7.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Insulin Sensitivity</title>
        <description>homeostasis model assessment-insulin resistance (HOMA-IR) HOMA-IR. Fasting insulin and glucose were be used to determine HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (µU/ml)]/22.5]&quot;, Optimal insulin sensitivity: &lt; 1, Early insulin resistance: &gt; 1.9, Significant insulin resistance: &gt; 2.9</description>
        <time_frame>6 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>rs174535 (GG), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O2">
            <title>rs174535 (GG), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O3">
            <title>rs174535 (GT), Fish Oil Supplements</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O4">
            <title>rs174535 (GT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
          <group group_id="O5">
            <title>rs174535 (TT), Fish Oil Supplement</title>
            <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
          </group>
          <group group_id="O6">
            <title>rs174535 (TT), Placebo</title>
            <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Insulin Sensitivity</title>
          <description>homeostasis model assessment-insulin resistance (HOMA-IR) HOMA-IR. Fasting insulin and glucose were be used to determine HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (µU/ml)]/22.5]&quot;, Optimal insulin sensitivity: &lt; 1, Early insulin resistance: &gt; 1.9, Significant insulin resistance: &gt; 2.9</description>
          <units>HOMA-IR Index</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="24"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="22"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="16"/>
                <count group_id="O6" value="18"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.67" spread="0.56"/>
                    <measurement group_id="O2" value="0.98" spread="0.92"/>
                    <measurement group_id="O3" value="0.67" spread="0.57"/>
                    <measurement group_id="O4" value="1.01" spread="1.33"/>
                    <measurement group_id="O5" value="0.72" spread="0.75"/>
                    <measurement group_id="O6" value="0.80" spread="0.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <desc>For the purposes of this study and adverse event is defined as any untoward medical occurrence in a subject, not necessarily having a causal relationship with the study. A serious adverse event (SAE) is any untoward medical occurrence that a) results in death, b) is life-threatening, c) requires inpatient hospitalization or prolongation of existing hospitalization, d) results in persistent or significant disability/incapacity, or e) is a congenital anomaly/birth defect.</desc>
      <group_list>
        <group group_id="E1">
          <title>rs174535 (GG), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="E2">
          <title>rs174535 (GG), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="E3">
          <title>rs174535 (GT), Fish Oil Supplements</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="E4">
          <title>rs174535 (GT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
        <group group_id="E5">
          <title>rs174535 (TT), Fish Oil Supplement</title>
          <description>Eicosapentanoic acid and docosahexanoic acid&#xD;
Eicosapentanoic acid and docosahexanoic acid: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks</description>
        </group>
        <group group_id="E6">
          <title>rs174535 (TT), Placebo</title>
          <description>Oleic Acid&#xD;
Oleic Acid: Placebo</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Myocardial Infarction</sub_title>
                <description>Study subject presented to emergency room with chest pain. The subject was admitted and diagnosed with a myocardial infarction. This was a serious adverse events but deemed not related to study participation</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="19"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating and eructations</sub_title>
                <description>Unable to tolerate the medication due to gastrointestinal side effects involving bloating and eructations</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="26"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="25"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="26"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="19"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Did not reach target accrual rate in T/T arm</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Harvey J Murff</name_or_title>
      <organization>Vanderbilt University Medical Center</organization>
      <phone>615 936 8319</phone>
      <email>harvey.j.murff@vanderbilt.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01661764
org study id: 11165
secondary id: R01CA160938
nct id: NCT01661764
lead sponsor: 
collaborator: 
has dmc: Yes
Colorectal cancer is the second leading cause of cancer-related death within the United
      States. Animal models and observational studies have suggested that marine-derived n-3
      polyunsaturated fatty acids [PUFA] such as eicosapentanoic acid [EPA] and docosahexanoic acid
      [DHA] may reduce the risk of colorectal cancer. In addition, it may be the relative
      proportion of n-3 to n-6 PUFAs that best determines the chemopreventive effects of fish oils.
      This ratio is important because the n-6 PUFA, arachidonic acid (ARA), is converted via the
      cyclo-oxygenase (COX) pathway to prostaglandin E2 (PGE2), an inflammatory eicosanoid
      overproduced in colorectal neoplasms while EPA is converted to the anti-inflammatory
      prostaglandin E3 (PGE3). While the ratio of n-6 to n-3 PUFAs can be altered through dietary
      changes, genetic factors may also influence this ratio. Recent genetic studies have
      demonstrated that much of the tissue levels of ARA is determined by differences in a gene
      called fatty acid desaturase 1 (FADS1). FADS1 is the rate-limiting enzyme in the conversion
      of linoleic acid, the most commonly consumed PUFA in the Western diet, to ARA, and one
      particular genetic variant caller rs174537 is associated with lower fatty acid desaturase
      activity and subsequently lower tissue levels of ARA.

      The study hypothesis is that individuals with genetically determined lower activity of FADS1
      will derive greater benefit from fish oil supplementation than individuals with higher FADS1
      activity because of lower tissue levels of ARA and subsequently a more favorable n-6 to n-3
      PUFA ratio. To test this hypothesis the investigators will recruit 150 participants with
      recently identified adenomatous polyps and conduct a 6-month double blind 3 X 2 factorial
      randomized controlled trial. The first factor will be FADS1 genotype (GG, GT, and TT) and the
      second factor will be fish oil supplementation (fish oil versus placebo). The primary outcome
      will be the change in rectal epithelial cell growth and cell death. Secondary outcomes will
      include rectal epithelial cell expression of genes important in PGE2 production, rectal cell
      production of PGE2 and PGE3, rectal mucosal tissue levels of fatty acids, and changes in
      biomarkers of inflammation (C-reactive protein), adipokines (leptin, adiponectin), and
      markers of insulin sensitivity.

      The specific aims include: 1) to determine the efficacy of fish oil supplements on rectal
      epithelial cell proliferation indexes and markers of rectal crypt apoptosis, and 2) to
      determine the effect of genetically-determined fatty acid desaturase 1 activity on fish oil
      supplementation for colorectal cancer chemoprevention. The investigators long-term objectives
      are to determine genetic factors that might influence the efficacy of fish oil
      supplementation in order to conduct a more definitive adenoma recurrence trial using
      marine-derived n-3 PUFAs. The investigators anticipate that fish oil will have
      anti-neoplastic effect and individuals with low FADS1 activity will have a greater response
      compared to individuals with high FADS1 activity
1.Rationale and Specific Aims

      Colorectal cancer (CRC) is the third most common cancer and the second most frequent cause of
      cancer related mortality in the United States. Animal and human studies have suggested that
      the marine-derived n-3 polyunsaturated fatty acids (PUFAs), eicosapentanoic acid (EPA) and
      docosahexanoic acid (DHA), have cancer inhibitory properties while conversely, n-6 PUFAs such
      as arachidonic acid (ARA) may promote tumorigenesis. The mechanism behind these opposing
      effects is likely due to differences in the biological activity of their eicosanoids end
      products and their effects on chronic inflammation. Prostaglandin E2 (PGE2) is a
      pro-inflammatory eicosanoid that is aberrantly produced in both colorectal adenomas and
      cancer and is derived from ARA via the cyclo-oxygenase pathway. EPA is converted through the
      same pathway into prostaglandin E3, which has 4 to 7- fold less prostaglandin E receptor
      affinity, is less inflammatory, and may even be pro-apoptotic compared to PGE2. As such, it
      may be the ratio of ARA to EPA and DHA rather than the absolute levels of marine-derived n-3
      PUFAs that contribute most towards their antiproliferative and pro-apoptotic effects.

      The ratio of ARA to EPA + DHA can be manipulated through fish oil supplementation, however;
      genetic factors may play a key role on determining this ratio. Recent genome-wide association
      and haplotype studies have demonstrated that up to 28% of the additive variance in tissue
      levels of ARA is explained by variants in a single gene, fatty acid desaturase 1 (FADS1).
      FADS1 is the rate-limiting enzyme in the conversion of linoleic acid (LA), the most commonly
      consumed PUFA, to ARA, and homozygotes for the T allele (population frequency of 13%, HapMap
      -CEU) in rs174537 have lower fatty acid desaturase activity and subsequently lower tissue
      levels of ARA. While EPA can be produced in vivo from α-linolenic acid, in humans, this
      process is extremely inefficient and most tissue level EPA derives directly from dietary
      consumption of fatty fish. Thus, high activity of FAD1 and subsequently increased tissue
      levels of ARA may offset some of the potential benefits of dietary supplementation with fish
      oil. To date, no previously published studies have investigated how genetic variants that
      influence fatty acid desaturase activity might modify the beneficial effects of fish oil
      supplementation.

      The investigators hypothesis is that the individuals with genetically determined lower
      activity of FADS1 will derive greater benefit from fish oil supplementation than individuals
      with higher FADS1 activity because of lower tissue levels of ARA and subsequently a more
      favorable ARA to EPA + DHA ratio. To test this hypothesis the investigators will recruit 150
      participants with recently identified adenomatous polyps and conduct a 6-month double blind 3
      X 2 factorial randomized controlled trial. The first factor will be the rs174537 genotype
      (GG, GT, and TT) in the FADS1 gene and the second factor will be fish oil supplementation
      (fish oil versus placebo). The primary study outcome will be the change from baseline in
      rectal epithelial cell proliferation as measured by Ki-67 labeling and rectal crypt apoptosis
      as measured by TUNEL. Secondary endpoints will include rectal epithelial cell expression of
      COX-2 and 15-PGDH, rectal cell production of PGE2 and PGE3, rectal cell fatty acid
      concentrations, as well as, changes from baseline in biomarkers of inflammation (C-reactive
      protein), adipokines (leptin, adiponectin), and markers of insulin sensitivity (HOMA-IR).

      The Specific Aims for this research proposal are:

        1. to determine the efficacy of fish oil supplements on rectal epithelial cell
           proliferation indexes and markers of rectal crypt apoptosis; and,

        2. to determine the effect of genetically determined fatty acid desaturase activity on fish
           oil supplementation for markers of colorectal cancer risk.

      The investigators long-term objectives are to determine genetic factors that might influence
      the efficacy of fish oil supplementation in order to conduct a more definitive adenoma
      recurrence trial using marine-derived n-3 PUFAs. The investigators anticipate that fish oil
      will have anti-neoplastic effect and individuals with low FADS1 activity will have a greater
      response compared to individuals with high FADS1 activity. This study will be the first to
      investigate the nutrigenomics of fish oil supplementation in colorectal cancer
      chemoprevention and may have implications beyond cancer prevention as fish oil is being
      actively investigated for its anti-inflammatory effects in cardiovascular and psychiatric
      diseases as well as diabetes mellitus and the metabolic syndrome.

      2. Recruitment and Retention

      The investigators will identify eligible participants based on the inclusion criteria by
      reviewing study data and medical record data collected in the Tennessee Colorectal Polyp
      Study(TCPS). Participants still eligible after record review will be mailed an introductory
      letter inviting them to participate. One week after the letter is mailed; a trained
      interviewer from the Vanderbilt Survey Research Shared Resource (SRSR) will call the
      potential participants to provide more detailed information about the study, answer questions
      about the study, and to see if they may be interested in participating. At that time, an
      appointment will be made with the participant for the baseline in-person visit. After the
      initial visit and informed consent is obtained an interviewer from the SRSR will conduct the
      baseline interview survey and 24-hour dietary recalls. At the baseline visit, the
      investigators will re-genotype rs174535 to confirm the accuracy of the imputation process.
      This strategy will allow the investigators to efficiently and accurately identify appropriate
      candidates for our study.

      Eligible subjects will present to the Vanderbilt General Clinical Research Center (GCRC) for
      the initial visit and baseline study procedures. Participants who are eligible for the study
      and provide written consent for enrollment will have blood obtained; an adipose tissue biopsy
      performed, and undergoes the baseline rectal mucosal biopsy procedure. Treatment assignment
      will be obtained from the Vanderbilt Investigational Pharmacy by a coordinator. The first
      dose of the study medication will be given to patients at the initial visit and the date and
      time recorded. This date and time will be considered the time of randomization.

      3. Randomization

      Randomization will be performed according to a permuted block randomization scheme stratified
      on the three genotypes. Randomization will proceed within these three strata with a block
      size of balancing interval, varying randomly according to the outcome of a computer generated
      random number. This ensures that the cumulative proportion of assignments to each treatment
      will be balanced after each block of assignments has been made.

      4. Study Procedures

        1. Data Collection

           Because outside dietary exposure to both n-6 and n-3 PUFAs could possibly confound the
           effect of fish oil supplementation the investigators will perform a total of four
           24-hour dietary recall studies for each participant over the course of the study. At
           enrollment, the investigators will conduct two 24-hour dietary assessments, one on the
           weekday and one on the weekend, as participants' diet may differ based on the day of the
           week. In addition the investigators will conduct one 24-hour dietary recall at week 8
           and at week 16. The investigators will use data collected from these 24-hour dietary
           assessments along with standard food composition tables to calculate dietary exposure to
           PUFAs.

           The investigators will determine adherence to study drug at each in-person visit during
           the study. Medication and medication changes will be recorded at these visits. Patients
           who initiate a new NSAID during the study will be withdrawn and an exit visit performed.
           Adherence to fish oil will also be determined through RBC phospholipid membrane fatty
           acid analysis performed at month 3 and month 6. In addition, to determine whether fish
           oil supplementation also influences fatty acid membrane concentration at the target
           tissue, the investigators will determine the change in rectal epithelial cell
           phospholipid membrane fatty acid concentration.

        2. Fish oil Capsules

           Participants allocated to fish oil supplementation will be instructed to take three
           Lovaza® capsules each containing 465 mg of EPA and 375 mg DHA daily; this will provide a
           total daily dose of 1395 mg EPA plus 1125 mg DHA for a total daily dose of fish oil of
           2.5 grams. Patients will take one tablet three times a day with meals. Lovaza® capsules
           are the only FDA approved preparation of fish oil, and as such, the quality of the drug
           is monitored and assured. Pharmacological grade fish oil capsules have the advantage of
           providing high concentrations of PUFAs, low levels of contaminants, such as mercury, and
           almost no fish odor.

        3. Placebo Capsules

           The investigators will use oleic acid as a placebo. The reason for the use of oleic acid
           is several-fold. First, oleic acid (olive oil) capsules have a similar texture, size,
           color, and consistency to fish oil capsules. More importantly, oleic acid does not
           undergo conversion to an eicosanoid or any other metabolically active product. This is
           opposed to corn oil, which has also been used as a placebo in fish oil studies but is
           primarily linoleic acid and could subsequently increase tissue levels of ARA and
           confound the results of our study. Oleic acid has been used as a placebo in several
           prior studies of fish oil supplementation and is well tolerated.

        4. Assessment Visits

      Patients will attend the GCRC clinic at the baseline (initial visit), after 3 months of study
      treatment (mid-point visit), and after 6 months of study treatment (end visit). The study
      coordinator will contact participants every 4 weeks over the course of the study to encourage
      adherence to the study protocol. At the 3-month and 6-month visits, compliance with treatment
      will be monitored by capsule count and measurement of RBC phospholipid fatty acid
      concentrations. Adverse events will be recorded at these visits.

      5. Data management and quality control

      The Vanderbilt GCRC Informatics Core will be used as a central location for data processing
      and analysis. Vanderbilt University has developed software tools and workflow methodology for
      electronic collection and management of research study data. (132) REDCap (Research
      Electronic Data Capture) is a secure, web-based application that provides an intuitive
      interface for users to enter validated data remotely (with automated data type and range
      checks), data manipulation audit trails and reporting, and an export mechanism for
      end-of-study export of data to common statistical packages.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Rectal Epithelial Cell Proliferation
time frame: 6 month
description: The primary outcome of interest is rectal epithelial cell proliferation, as measured by Ki67 (mib-1) labeling. Expression of Ki-67 in colon epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
measure: Rectal Epithelial Cell Apoptosis
time frame: 6 months
description: The primary outcome of interest is rectal epithelial cell apoptosis as measured by TUNEL (TdT-mediated dUTP Nick-End Labeling). The TUNEL assay is conducted to measure apoptosis of colon epithelium using DeadEnd Colorimetric TUNEL System (Promega). After all fields of each sample are measured, the final immunoreaction indices are generated automatically by setting algorithms as ''total positive area / total nuclear area. Apoptotic activity is also scored using standard morphologic criteria applied to H&E stained sections.
measure: Rectal Epithelial Cell COX-2 Expression
time frame: 6 months
description: Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
measure: Rectal Epithelial Cell 15-PGDH Expression
time frame: 6 months
description: Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).
measure: Rectal Epithelial Cell Phospholipid Fatty Acid Content
time frame: 6 months
description: Lipids will be extracted using the method of Folch-Lees
measure: Rectal Epithelial Cell Production of PGE2 and PGE3
time frame: 6 months
description: liquid chromatography/tandem mass spectrometric on rectal biopsy samples
measure: C-reactive Protein
time frame: 6 months
measure: Adipokines
time frame: 6 months
description: leptin and adiponectin
measure: Insulin Sensitivity
time frame: 6 months
description: homeostasis model assessment-insulin resistance (HOMA-IR) HOMA-IR. Fasting insulin and glucose were be used to determine HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (µU/ml)]/22.5]", Optimal insulin sensitivity: < 1, Early insulin resistance: > 1.9, Significant insulin resistance: > 2.9
arm group label: rs174535 (GG), fish oil supplements
arm group type: Active Comparator
description: Eicosapentanoic acid and docosahexanoic acid
arm group label: rs174535 (GG), placebo
arm group type: Placebo Comparator
description: Oleic Acid
arm group label: rs174535 (GT), fish oil supplements
arm group type: Active Comparator
description: Eicosapentanoic acid and docosahexanoic acid
arm group label: rs174535 (GT), placebo
arm group type: Placebo Comparator
description: Oleic Acid
arm group label: rs174535 (TT), fish oil supplement
arm group type: Active Comparator
description: Eicosapentanoic acid and docosahexanoic acid
arm group label: rs174535 (TT), placebo
arm group type: Placebo Comparator
description: Oleic Acid
intervention type: Drug
intervention name: Eicosapentanoic acid and docosahexanoic acid
description: 1395 mg EPA plus 1125 mg DHA daily for 24 weeks
arm group label: rs174535 (GG), fish oil supplements
arm group label: rs174535 (GT), fish oil supplements
arm group label: rs174535 (TT), fish oil supplement
other name: Lovaza
intervention type: Drug
intervention name: Oleic Acid
description: Placebo
arm group label: rs174535 (GG), placebo
arm group label: rs174535 (GT), placebo
arm group label: rs174535 (TT), placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 79 Years
healthy volunteers: No
last name: Harvey J Murff, MD, MPH
role: Principal Investigator
affiliation: Vanderbilt University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University
investigator full name: Harvey Murff
investigator title: Associate Professor
mesh term: Adenomatous Polyps
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Did not reach target accrual rate in T/T arm
point of contact: 