Ignite Creation Date:
2024-05-06 @ 12:49 AM
Last Modification Date:
2024-10-26 @ 10:55 AM
Study NCT ID:
NCT01661764
Status:
COMPLETED
Last Update Posted:
2018-06-08
First Post:
2012-08-07
Brief Title:
Fish Oil Supplementation Nutrigenomics and Colorectal Cancer Prevention
Sponsor:
Vanderbilt University
Organization:
Vanderbilt University Medical Center
Study Overview
Official Title:
Fatty Acid Desaturase Activity Fish Oil and Colorectal Cancer Prevention
Status:
COMPLETED
Status Verified Date:
2018-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
1Rationale 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 StudyTCPS 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 25 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
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 StudyTCPS 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 25 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| R01CA160938 | NIH | None | httpsreporternihgovquickSearchR01CA160938 |