Vitamin D/Calcium Polyp Prevention Study

This study is a double-blind, placebo-controlled trial of vitamin D and/or calcium
supplementation for the prevention of large bowel adenomas. Subjects will be recruited from
11 Study Centers in North America. Eligible subjects will have had at least one large bowel
adenoma removed in the 4 months prior to study entry and no remaining polyps in the bowel
after complete colonoscopic examination. Participants will be randomized in a partial 2 x 2
factorial design to vitamin D (1000 IU/day), calcium carbonate (1200 mg elemental
calcium/day), both agents, or placebo only (Full Factorial randomization). Women who decline
to forego calcium supplementation will be randomized only to calcium alone or to calcium plus
vitamin D (Two Arm randomization). Randomization will be stratified by gender, study center
of recruitment, and anticipated follow-up interval (see below), and will be conducted
separately for female subjects randomized only to vitamin D. We anticipate enrolling up to
3000 participants to reach a total of up to 2400 randomized subjects. As safety measures,
blood levels of calcium, creatinine, and 25-(OH)-vitamin D will be obtained at baseline and 1
year after randomization, as well as 3 years after randomization for subjects with a 5-year
surveillance cycle. Every six months after randomization subjects will complete a
questionnaire regarding compliance with study agents, use of medications and vitamin/mineral
supplements, illnesses, hospitalizations, and dietary intake of calcium and vitamin D. The
primary endpoint of the study will be new adenomas detected on follow-up colonoscopy. These
examinations are scheduled to occur either 3 years or 5 years after the qualifying
examination, depending on the follow-up interval recommended by each patient's endoscopist.
Some patients may, for medical reasons, have a colonoscopy at a time other than 3 or 5 years
after the qualifying examination. Information from these exams will be included in analyses
where appropriate. In the primary analyses, the occurrence of new adenomas in the interval
between randomization and the follow-up exam will be compared between subjects randomized to
vitamin D (with or without calcium) versus those randomized to no vitamin D (with or without
calcium), between subjects randomized to calcium (with or without vitamin D) versus those
randomized to no calcium (with or without vitamin D; excluding women electing to receive
calcium who therefore cannot participate in the calcium component of the study), and between
those randomized to calcium plus vitamin D versus those randomized to calcium alone. In
secondary analyses, we will examine the impact of baseline vitamin D levels and vitamin D
receptor (VDR) polymorphisms on the vitamin D effects. Effects on advanced adenomas will also
be assessed as a secondary outcome. Participants will be invited to participate in an
optional Observational Follow Up phase of the study that will begin following the end of
treatment. In this phase of the study, subjects will continue to be followed on an
observational basis (no study treatment) with annual questionnaires until the time of a
subsequent colonoscopy that is at least three years from the follow up colonoscopy at which
study treatment was ended. We will examine the occurrence of new adenomas in the interval
between the colonoscopy exam at the end of study treatment and the exam at the end of
observational follow up period.

Inclusion Criteria:

- One or more histologically verified neoplastic polyp (adenoma) that is at least 2 mm
in size removed from the large bowel with the entire large bowel examined by
colonoscopy and documented to be free of further polyps or areas suspicious for
neoplasia within 120 days of study entry

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

- Age between 45 and 75 years at enrollment

- (Women)Agreement to avoid pregnancy (i.e., use of standard contraception)

- Willingness to forego calcium supplementation (including multivitamins containing
calcium) or, for women only, option of taking calcium supplementation of 1200 mg/daily
(contained in the study pills)

- Willingness to forego vitamin D supplementation (including multivitamins containing
vitamin D)

- Agreement to daily dietary intake of the equivalent of not more than 1200 mg calcium

- Agreement to daily dietary intake of the equivalent of not more than 400 IU vitamin D

- Blood calcium level within normal range

- Blood creatinine level not to exceed 20% above upper limit of normal

- Serum 25-(OH)-vitamin D within lower limit of normal to 70 ng/ml

- Ability and willingness to follow the study protocol, as indicated by provision of
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

Exclusion Criteria:

General exclusionary criteria:

- Participation in another colorectal (bowel) study (intervention study) in the past 5
years

- Current participation in any other clinical trial (intervention study)

- Pregnancy or lactation

- A diagnosis of narcotic or alcohol dependence in the past 5 years

- A diagnosis of dementia (e.g. Alzheimer's) in the past 5 years

- A diagnosis of a significant psychiatric disability (e.g. Schizophrenia, refractory
bipolar disorder, current severe depression) in the past 5 years

Exclusions due to derangement of calcium metabolism or indications /contraindications to
study agents:

- Any diagnosis of kidney stones

- A diagnosis of granulomatous diseases, e.g. sarcoidosis, active chronic fungal or
mycobacterial infections (tuberculosis, histoplasmosis, coccidioidomycosis,
blastomycosis), berylliosis, Wegener's granulomatosis in the past 5 years

- A diagnosis of hyperparathyroidism or other serious disturbance of calcium metabolism
in the past 5 years

- A diagnosis of severe kidney disease, e.g. chronic renal failure in the past 5 years

- A diagnosis of unexplained hypercalcemia in the past 5 years

- Any Diagnosis of osteoporosis with physician recommendation for treatment of low bone
mass

- A diagnosis of two or more low trauma fractures in the past 5 years

- A diagnosis of a medical condition requiring treatment with vitamin D (e.g.
osteomalacia) in the past 5 years

Exclusions due to intestinal or bowel problems:

- Any diagnosis of invasive carcinoma of the large bowel (even if confined to a polyp)

- Any diagnosis of familial colorectal cancer syndromes, e.g. Familial Adenomatous
Polyposis (FAP) (including Gardner syndrome, Turcot's syndrome), Hereditary
Nonpolyposis Colorectal Cancer (HNPCC), Hamartomatous Polyposis syndromes (including
Peutz-Jeghers or Familial Juvenile Polyposis)

- Any diagnosis of inflammatory bowel disease, e.g. Crohn's Disease, Ulcerative Colitis

- A diagnosis of chronic intestinal malabsorption syndromes, e.g. celiac sprue,
bacterial overgrowth, chronic pancreatitis, pancreatic insufficiency in the past 5
years

- Any large bowel resection

Exclusions due to poor health:

- A diagnosis of malignancy, other than non-melanoma skin cancer in the past 5 years

- A diagnosis of severe lung disease - class 3 or 4 (e.g. chronic obstructive pulmonary
disease or emphysema requiring oxygen) in the past 5 years

- A diagnosis of severe heart disease: cardiovascular disease functional class 3 or 4 in
the past 5 years

- Any diagnosis of severe liver disease, e.g. cirrhosis

Exclusions due to shipping regulations:

- Any current/past HIV positive diagnosis

- Active hepatitis B, defined as : Hep B surface antigen positive

- Active hepatitis C, defined as : measurable hepatitis C RNA

Drug exclusions:

- Use of chronic oral corticosteroid therapy in the past 5 years

- Use of lithium in the past 5 years

- Use of phenytoin's in the past 5 years

- Use of quinidine in the past 5 years

- Use of therapeutic vitamin D in the past 5 years