Calcium/Vitamin D, Biomarkers & Colon Polyp Prevention

This study is an add-on study ('adjunct study') to a clinical trial that is already being
conducted (the 'parent study'). Study participants will be composed of persons who are
already participating in the parent study, "Vitamin D/Calcium Polyp Prevention Study". In
the parent study, a total of 1,964 people nationally are being randomly assigned to four
different treatment groups: 1) calcium supplements, 600 mg twice a day; 2) vitamin D
supplements, 500 IU twice a day; 3) both the calcium and vitamin D supplements twice a day;
and 4) placebo tablets twice a day. The treatment period lasts three to five years at the
end of which study participants undergo a follow-up colonoscopy to look for new polyps. The
parent study began about a year prior to the start of this adjunct study, thus, there are
already some patients in the trial who are receiving their study 'treatments' (i.e., have
been 'randomized'), but more patients will be recruited into the parent study.

Depending on whether someone has already been randomized, participants of the parent study
will be invited to take part in the adjunct study in one of two ways: 'Aim 1' only, or 'All
Aims'. First, patients who have already been randomized will be asked to allow biopsies to
be made of their rectal tissue during their 3- or 5-year follow-up colonoscopy (Aim 1).
Biopsies, which will be used for our biomarker measurements, are very tiny pieces of tissue
that can be examined under the microscope. Second, patients who have not yet been randomized
will be invited to participate more fully (All Aims) in the adjunct study. This involves
having outpatient rectal biopsies taken immediately after their first phone call, their
1-year follow-up visit, and 7 - 21 days before their 3- or 5-year follow-up colonoscopy.
Finally, during their 3- or 5-year colonoscopy, biopsies will be taken from three areas of
the colon: the rectum (same area as the outpatient biopsies), the sigmoid colon, and the
ascending colon. From all of the biopsies taken from all of the visits and colon sites,
biomarker measurements will be of normal proteins that occur in the surface cells lining the
colon. Study researchers will then analyze whether calcium and/or vitamin D affect these
biomarkers and whether the effects predict who gets new polyps.

Currently participating in the parent study. Not open to people not already enrolled in
the parent study. This sub-study is for the collection of biopsies only, while the parent
study is for calcium and vitamin D to prevent reoccurrence of colon polyps.

Inclusion Criteria for the parent study:

- 45 - 75 years old.

- ≥ 1 histologically-verified neoplastic polyps, ≥ 2 mm in diameter, removed from the
large bowel within 4 months of study entry, with entire large bowel examined by
colonoscopy and documented free of further polyps.

- Willing to follow the study protocol, as indicated by the subject's informed consent
to participate.

- Good general health, with no severely debilitating diseases or active malignancy that
might compromise the patient's ability to complete the study.

- Anticipated colonoscopic follow up three years or five years after the qualifying
colonoscopy.

Exclusion Criteria for the parent study:

- Invasive carcinoma in any colonic polyp removed.

- Familial colonic polyposis syndromes.

- Ulcerative colitis or Crohn's disease.

- Malabsorption syndrome (e.g., pancreatic insufficiency).

- History of large bowel resection for any reason.

- Diagnosed narcotic or alcohol dependence.

- Elevated serum calcium or creatinine, or supraphysiologic levels of 25(OH) vitamin D
at study entry.

- Current use of thiazide diuretic in amount greater than the equivalent of 50 mg of
hydrochlorothiazide.

- New York Heart Association Cardiovascular Disease functional class 3 or 4.

- On renal dialysis.

- History of kidney stones, unexplained hematuria, or sarcoidosis in the previous 20
years.

- Any history of hypo- or hyperparathyroidism.

- Unwilling to forgo individual calcium and vitamin D supplementation during the trial.

- Unwilling to forgo daily intake of more than a quart of milk (or equivalent in other
dairy products) or daily dietary intake of vitamin D estimated to be greater than 400
IU.

- History of osteoporosis or other medical condition that may require supplemental
calcium or vitamin D.

- Current use of bisphosphonates (eg, alendronate [Fosamax], risendronate [Actonel]).

- Current use of calcitonins (eg, Miacalcin).

Additional exclusion criteria for the adjunct biomarker study are:

- Unable to be off aspirin for 7 days.

- History of bleeding disorder or current use of anticoagulant medication.