Neoplasms

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Adenomatous Polyposis Coli

Polyps

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Gastrointestinal Neoplasms

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Gastrointestinal Diseases

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Rectal Diseases

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Adenomatous Polyps

Adenoma

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Genetic Diseases, Inborn

Familial Adenomatous Polyposis

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Other Dietary Supplements

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Omega 3 Fatty Acid

Cola

Eicosapentanenoic Acid (EPA) as the free fatty acid 2 capsules twice daily for 6 months.

Endoscopy and biopsies taken as described under intervention.

Medium chain triglycerides 2 capsules twice daily for six months. Endoscopy and biopsies taken as described under intervention.

2 x 500mg EPA capsules twice daily for 6 months

Eicosapentanoic Acid (EPA)

Endoscopy with video and photographs at baseline and month 6.

Endoscopy

9 biopsies taken at baseline and month 6 from the rectum of normal mucosa for analysis of apoptosis (3 biopsies), cell proliferation (3 biopsies) and mucosal fatty acid levels (3 biopsies). Two biopsies taken at baseline and month 6 from polyps for cell proliferation (1 biopsy) and apoptosis (1 biopsy).

Biopsies taken

2 x 500mg placebo capsules twice daily for 6 months

Placebo

Nicholas J West, MB BS FRCS

This purpose of this study is to investigate whether the number and size of rectal polyps can be reduced in patients with Familial Adenomatous Polyposis (FAP) by using a highly-purified form of a naturally occurring substance, the omega-3 fatty acid, eicosapentaenoic acid (EPA).

It has been found that people who consume a large amount of oily fish tend to have a lower risk of developing colon cancer. This is thought to be due to the omega-3 fatty acids present in oily fish, one of which is EPA. The effect of taking a 99% pure form of EPA (2g per day) compared with placebo capsules on the number and size of polyps in the rectum over a six month period will be investigated.

FAP is an inherited susceptibility to diffuse colorectal adenomas and colorectal carcinoma, occurring in close to 100% of unresected colons. It is caused by a germline mutation in the Adenomatous Polyposis Coli (APC) gene located in the long arm of chromosome 5. To prevent cancer development it is recommended that patients with FAP undergo colectomy with ileo-anal or ileo-rectal anastomosis (or colectomy and end-ileostomy) at a socially convenient time before polyp progression to malignancy and before the age of 25. Patients with the attenuated FAP phenotype, often associated with mutations at the 5' terminus (exon 4 and proximally), have fewer polyps and may often delay colectomy. Patients with an ileo-rectal anastomosis are still susceptible to polyp formation in the remaining rectal stump and require 6 monthly check-ups with a flexible sigmoidoscope with removal of any polyps that develop. Therefore, an effective chemopreventative agent with a favourable side-effect profile would be of benefit to FAP patients with ileo-rectal anastomosis (IRA) and recurrent rectal polyps in addition to young adults who prefer to delay colectomy. If such an agent were to be effective in FAP patients in the prevention of colonic polyps, it may also be of benefit to the larger population of patients with sporadic colorectal adenomatous polyps who are also at risk of colorectal cancer.

Colorectal polyps are thought, at least in part, to arise from an imbalance in the levels of cell proliferation and apoptosis (natural cell death) in the colonic mucosa. It has been suggested that omega-3 polyunsaturated fatty acids (PUFAs) in fish oil can manipulate the high levels of colonic-mucosal cell proliferation rates associated with colonic adenomas.

The rationale for this trial is based on the increasing evidence linking inflammatory processes and the development of a number of cancers, including bowel cancer. This has focused attention on the role of inflammatory mediators in the development of cancer. In particular, the family of eicosanoids (including 2-series prostaglandins, 4-series leukotrienes and thromboxanes) produced through conversion of the omega-6 PUFA, arachidonic acid, via cyclo-oxygenase-2 (COX-2) is believed to contribute to the physiological processes of inflammation and the development of tumours. Prostaglandin E2, a product of the conversion of arachidonic acid via the COX-2 pathway, has been implicated in tumourigenesis through:

1. promotion of angiogenesis
2. anti-apoptotic properties
3. increasing expression of matrix metalloproteinases and hence the ability of a tumour cell to undergo metastasis
4. altering the cytokine expression profile of cells.

The class of eicosanoid synthesised will depend on the PUFA substrate. Whilst arachidonic acid is converted to 2-series prostaglandins and 4-series leukotrienes, EPA is converted to 3-series prostaglandins and 5-series leukotrienes. Overall, the latter eicosanoids are less potent as inflammatory mediators than those derived from arachidonic acid.

Increasing daily intake of EPA, the omega-3 PUFA analogue of arachidonic acid, alters the balance between the cell content of these fatty acids. This results in reduced production of the more active inflammatory/tumourigenic products of arachidonic acid metabolism. This is supported by the results of recent work at St George's Hospital Medical School, London. In patients with a history of colonic adenomas, daily dosing with a highly purified, free-fatty acid form of the EPA produced a significant reduction in cell proliferation and increase in apoptosis in the colonic mucosa. This preparation of EPA has the proprietary name "Alfa" and is referred to here as EPA.

This proposed study will be based upon the randomised, placebo-controlled National Cancer Institute sponsored study in which three groups of FAP patients were assigned to one of two doses of celecoxib (a COX-2 inhibitor) or placebo. The results showed a reduction in the polyp burden of the group taking the higher (400mg twice daily (bd)) dose. However, there is evidence to suggest that COX-2 inhibitors carry significant potential for side-effects. Adopting a similar design, EPA will be substituted for celecoxib in this randomised, placebo-controlled trial, comparing 2g EPA to placebo, with reduction in polyp burden as the primary objective.

Chemoprevention Trial in Familial Adenomatous Polyposis (FAP) Coli Using EPA

A Two-Arm Chemoprevention Trial in Familial Adenomatous Polyposis (FAP) Coli Patients Using the Purified Free Fatty Acid, Eicosapentaenoic Acid

Absolute change in the number of polyps measured in a defined focal area of the rectum.

Percentage change in the number of polyps measured in the defined focal area of the rectum in subjects treated with EPA compared to subjects receiving placebo.

Change in global rectal polyp burden in subjects treated with Eicosapentanoic Acid (EPA) compared to subjects receiving placebo. Each reviewer in the Polyp Video Scoring Committee assessed global colorectal polyp burden change as "better", "same as" or "worse". The qualitative assessment was assigned a score of +1 for "better", 0 for "same as" and -1 for "worse". Thereafter a mean overall reviewers score was calculated.

Relative EPA concentration of total free fatty acids in the rectal mucosa of subjects with FAP.

Incidence of adverse events in each treatment group.

S.L.A. Pharma AG

Eicosapentanoic Acid (EPA): 2 x 500mg EPA capsules twice daily for 6 months

Endoscopy: With video and photographs at baseline and month 6.

Biopsies taken: 9 biopsies taken at baseline and month 6 from the rectum of normal mucosa for analysis of apoptosis (3 biopsies), cell proliferation (3 biopsies) and mucosal fatty acid levels (3 biopsies). Two biopsies taken at baseline and month 6 from polyps for cell proliferation (1 biopsy) and apoptosis (1 biopsy).

2g/Day Eicosapentanoic Acid (EPA)

Medium chain triglycerides 2 capsules twice daily for six months.

Endoscopy: With video and photographs at baseline and month 6.

Biopsies taken: 9 biopsies taken at baseline and month 6 from the rectum of normal mucosa for analysis of apoptosis (3 biopsies), cell proliferation (3 biopsies) and mucosal fatty acid levels (3 biopsies). Two biopsies taken at baseline and month 6 from polyps for cell proliferation (1 biopsy) and apoptosis (1 biopsy).

2g/Day EPA

Total

Age, Continuous

Age, Categorical

Sex: Female, Male

United Kingdom

Region of Enrollment

The baseline characteristics are presented for the full analysis set which constitutes 55 of the 58 randomised subjects. The full analysis set includes all subjects who were randomised into the study, took at least one dose of study medication provided both at baseline and at least one treatment measurement for efficacy.

Dr Chris Jordan

Eicosapentaenoic Acid (EPA) 2g per day for six months

2g/Day Eicosapentaenoic Acid (EPA)

Medium chain triglycerides 2g per day for six months

13 subjects lacked the photographs required for counting the measurements of polyps. Reasons for lack of photographs varied including failure of video equipment, inability to identify identical views of the focal area and no forceps visible for calibration.

Absolute Change in the Number of Polyps Measured in a Focal Area of the Rectum.

Percentage Change in the Number of Polyps Measured in the Defined Focal Area of the Rectum.

5 subjects in the full analysis set lacked the video required for determining global rectal polyp burden due to failure of equipment.

Change in Global Rectal Polyp Burden.

3 subjects in the full analysis set had no samples for analysis.

Relative EPA Concentration of Total Free Fatty Acids in the Rectal Mucosa.

Number of Subjects With Adverse Events.

Medium chain triglycerides 2 g per day for six months.

Overall Study

Colonic Polyps

Pathological Conditions, Anatomical

Hematinics

Anti-Infective Agents

Liver Extracts

Carbamide Peroxide

Either 2 x 500mg EPA capsules in the morning and evening (2g per day EPA) or 1 x 500mg EPA and 1 x placebo in the morning and evening (1g per day EPA)

Eicosapentaenoic Acid (EPA)

9 biopsies taken for measurement of apoptosis (3 biopsies), cell proliferation (3 biopsies) and fatty acid levels (3 biopsies) at baseline, month 3 and month 6.

Full blood count at baseline, month 3 and month 6.

Clinical chemistry

Urea and electrolytes, liver function tests, clotting profile and CRP at baseline, month 3 and month 6.

Haematology

Including cardio-respiratory and abdominal examination at baseline, month 3 and month 6.

Physical examination

Height, weight, heart rate, blood pressure and temperature at baseline, month 3 and month 6.

Vital signs

For subjects of child-bearing potential, urine pregnancy test at baseline, month 3 and month 6.

Urine pregnancy test

Subjects are requested to complete when study medication is taken and in any new or unusual symptoms are experienced on a daily basis for 6 months.

Completion of patient diary card

The purpose of this study is to determine the effect of two doses purified EPA (an omega-3 fatty acid), on apoptosis (natural cell death) and cell proliferation (formation of new cells) in the lining of the colon for patients with a history of colonic polyps.

Colorectal cancer is generally accepted to develop from changes within colonic adenomatous polyps. More than 90% of new large bowel cancers arise sporadically. The molecular events leading to the development of colorectal cancer from polyps are characterised by an imbalance in cell proliferation (formation of new cells) and apoptosis (natural cell death) from changes in the genes involved in normal colon cells.

Recent work at St George's Hospital Medical School, London, has shown significant beneficial effects on cell proliferation and apoptosis rates in the lining of the colon in subjects with a history of colonic adenomas using a highly purified, free-fatty acid form of eicosapentaenoic acid (EPA).

Comparator(s): 2g EPA per day for 6 months and 1g EPA per day for 6 months will be compared against placebo for 6 months.

Effect of 2 Doses of EPA on Apoptosis and Cell Proliferation on Colon Mucosa

The Effect of Two Dose Levels of Eicosapentaenoic Acid (EPA) on Apoptosis and Cell Proliferation in the Colonic Mucosa of Patients With a History of Colonic Polyps.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemoprevention Trial in Familial Adenomatous Polyposis (FAP) Coli Using EPA	NCT00510692	Familial Adenom... FAP	Eicosapentanoic... Endoscopy Biopsies taken Placebo	18 Years -	S.L.A. Pharma AG
Chemoprevention Trial in Familial Adenomatous Polyposis (FAP) Coli Using EPA	NCT00510692	Familial Adenom... FAP	Eicosapentanoic... Endoscopy Biopsies taken Placebo	18 Years -	S.L.A. Pharma AG
Effect of 2 Doses of EPA on Apoptosis and Cell Proliferation on Colon Mucosa	NCT00432913	Adenomatous Pol...	Eicosapentaenoi... Endoscopy Biopsies taken Clinical chemis... Haematology Physical examin... Vital signs Urine pregnancy... Completion of p...	18 Years -	S.L.A. Pharma AG

Spots Global Cancer Trial Database for biopsies taken