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Fish Oil Supplementation, Nutrigenomics and Colorectal Cancer Prevention

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ClinicalTrials.gov Identifier: NCT01661764
Recruitment Status : Completed
First Posted : August 9, 2012
Results First Posted : May 8, 2018
Last Update Posted : June 8, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Harvey Murff, Vanderbilt University

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Colorectal Adenomatous Polyps Drug: Eicosapentanoic acid and docosahexanoic acid Drug: Oleic Acid Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 141 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Fatty Acid Desaturase Activity, Fish Oil and Colorectal Cancer Prevention
Actual Study Start Date : February 4, 2013
Actual Primary Completion Date : December 26, 2016
Actual Study Completion Date : January 23, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Fish oil

Arm Intervention/treatment
Active Comparator: rs174535 (GG), fish oil supplements
Eicosapentanoic acid and docosahexanoic acid
Drug: Eicosapentanoic acid and docosahexanoic acid
1395 mg EPA plus 1125 mg DHA daily for 24 weeks
Other Name: Lovaza

Placebo Comparator: rs174535 (GG), placebo
Oleic Acid
Drug: Oleic Acid
Placebo

Active Comparator: rs174535 (GT), fish oil supplements
Eicosapentanoic acid and docosahexanoic acid
Drug: Eicosapentanoic acid and docosahexanoic acid
1395 mg EPA plus 1125 mg DHA daily for 24 weeks
Other Name: Lovaza

Placebo Comparator: rs174535 (GT), placebo
Oleic Acid
Drug: Oleic Acid
Placebo

Active Comparator: rs174535 (TT), fish oil supplement
Eicosapentanoic acid and docosahexanoic acid
Drug: Eicosapentanoic acid and docosahexanoic acid
1395 mg EPA plus 1125 mg DHA daily for 24 weeks
Other Name: Lovaza

Placebo Comparator: rs174535 (TT), placebo
Oleic Acid
Drug: Oleic Acid
Placebo




Primary Outcome Measures :
  1. Rectal Epithelial Cell Proliferation [ Time Frame: 6 month ]
    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).

  2. Rectal Epithelial Cell Apoptosis [ Time Frame: 6 months ]
    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.


Secondary Outcome Measures :
  1. Rectal Epithelial Cell COX-2 Expression [ Time Frame: 6 months ]
    Expression of COX-2 in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).

  2. Rectal Epithelial Cell 15-PGDH Expression [ Time Frame: 6 months ]
    Expression of 15-PGDH in rectal epithelial cells will be detected following the standard IHC protocol of EnVision™+ System, HRP (DAKO).

  3. Rectal Epithelial Cell Phospholipid Fatty Acid Content [ Time Frame: 6 months ]
    Lipids will be extracted using the method of Folch-Lees

  4. Rectal Epithelial Cell Production of PGE2 and PGE3 [ Time Frame: 6 months ]
    liquid chromatography/tandem mass spectrometric on rectal biopsy samples


Other Outcome Measures:
  1. C-reactive Protein [ Time Frame: 6 months ]
  2. Adipokines [ Time Frame: 6 months ]
    leptin and adiponectin

  3. Insulin Sensitivity [ Time Frame: 6 months ]
    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



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Ages Eligible for Study:   40 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ≥ 40 and < 80 years of age
  • History of 1 or more adenomatous polyps
  • Consent to be contacted for future studies
  • Participants with known genotype for rs174535 in FADS1
  • Prior participation in the Tennessee Colorectal Polyp Study or the Personalized Prevention of Colorectal Cancer Trial

Exclusion Criteria:

  • Previously resected colorectal cancer
  • Coronary artery disease or congestive heart failure
  • Current metabolic or life-threatening disease
  • Currently taking fish oil supplements
  • Inability or unwillingness to stop NSAIDs or ASA during the study
  • Allergic to fish products
  • Diagnosis of inflammatory bowel disease
  • Diagnosis of any cancer (except non-melanoma skin cancer)
  • Diagnosis of liver or kidney disease
  • Pregnant or breast feeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01661764


Locations
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United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Harvey J Murff, MD, MPH Vanderbilt University
  Study Documents (Full-Text)

Documents provided by Harvey Murff, Vanderbilt University:

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Responsible Party: Harvey Murff, Associate Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01661764     History of Changes
Other Study ID Numbers: 11165
R01CA160938 ( U.S. NIH Grant/Contract )
First Posted: August 9, 2012    Key Record Dates
Results First Posted: May 8, 2018
Last Update Posted: June 8, 2018
Last Verified: May 2018

Keywords provided by Harvey Murff, Vanderbilt University:
Colorectal Neoplasm

Additional relevant MeSH terms:
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Colorectal Neoplasms
Adenomatous Polyps
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type