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

Phase 2/Phase 3
18 Years
Not Enrolling
Familial Adenomatous Polyposis Coli, FAP

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Trial Information

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

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
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

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 99%.

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 99% will be substituted for celecoxib in this randomised,
placebo-controlled trial, comparing 2g EPA 99% to placebo, with reduction in polyp burden as
the primary objective.

Inclusion Criteria:

- Subjects must have a known diagnosis of FAP and have had a previous colectomy with
ileo-rectal anastomosis.

- Males or females aged 18 and over

- If the participant is female and of child bearing potential, she agrees to
participate in this study by providing written informed consent, has been using
adequate contraception (e.g. abstinence, condom, IUD, birth control pill, diaphragm
and spermicidal gel combination) since her last menses and will use adequate
contraception during the study, is not lactating, and agrees to undergo a serum
pregnancy test at baseline and month 6. Sexually active males must agree to use an
accepted method of contraception.

- Rectal polyp status: the subject has an endoscopically assessable rectal segment.

- Subjects must show a willingness to abstain from regular use of non-steroidal
anti-inflammatory medication for the duration of the study. A cardioprotective dose
of aspirin (75mg) will be permitted.

- Subjects must have provided written informed consent to participate.

- Subjects must have assessable rectal polyps post baseline flexible sigmoidoscopy.

- Subjects must have the following rectal polyp burden at the conclusion of the
baseline endoscopy:

- Rectum - 3 or more quantifiable polyps ≥2mm diameter

- In the rectum quantifiable polyps are defined as being within a composite
"cloverleaf" photograph that includes a tattoo.

Exclusion Criteria:

- Subjects who are due to undergo an anticipated colectomy within 8 months of

- History of invasive carcinoma in the past 5 years other than resected Dukes' A/B1
colon cancer or resected non-melanomatous skin cancer

- Partial or complete colectomy within 12 months prior to enrolment.

- History of pelvic radiation

- Subjects who are allergic to fish

- Subjects who have diabetes mellitus

- Subjects who are pregnant or breast-feeding

- Subjects taking aspirin or other non-steroidal anti-inflammatory drugs on a regular
basis other than low dose (75 mg) cardioprotective dose.

- Subjects who have aspirin-sensitive asthma

- Subjects suffering from haemorrhagic disorders

- Subjects who are taking warfarin or other anticoagulants

- Subjects who have significant abnormalities on their screening blood tests

- Subjects taking lipid lowering medication

- Subjects with gastrointestinal malabsorptive disease

- Subjects with known or prior coagulopathy

- Subjects with uncontrolled hypercholesterolaemia

- Subjects who are taking other fish-oil supplements (e.g. cod liver oil) who are
unwilling to stop them for the duration of the study. Subjects previously taking fish
oil must have a washout period of 1 month prior to study enrolment.

- Subjects who are deemed mentally incompetent, or have a history of anorexia nervosa
or bulimia

- Subjects with a history of alcohol or drug abuse, including laxative abuse which
would render the subject unreliable.

- Subjects considered by their physician unlikely to be able to comply with the

- Subjects who have taken part in an experimental drug study in the preceding 3 months.

- Subjects who have a positive pregnancy test within 14 days prior to baseline visit.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Outcome Measure:

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

Outcome Time Frame:

6 months

Principal Investigator

Nicholas J West, MB BS FRCS

Investigator Role:

Principal Investigator

Investigator Affiliation:

The Polyposis Registry, St. Mark's Hospital,


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

November 2006

Completion Date:

April 2008

Related Keywords:

  • Familial Adenomatous Polyposis Coli
  • FAP
  • Eicosapentaenoic Acid
  • EPA
  • EPA 99%
  • Fatty acid
  • omega-3
  • apoptosis
  • cell proliferation
  • colonic mucosa
  • polyp
  • Familial Adenomatous Polyposis Coli
  • FAP
  • resolvin
  • Ileo-rectal anastomosis
  • IRA
  • PUFA
  • Endoscopy
  • Adenomatous Polyposis Coli