Extensive experimental and observational data suggest that intake of calcium and of vitamin D exert protective effects on colorectal neoplasia. Building on our previous work, we will investigate the chemopreventive effect of vitamin D in the large bowel, to study whether calcium with vitamin D is more effective than calcium alone, and to confirm our positive finding regarding calcium. Our goal is the development of chemopreventive combinations that will reduce risk of colorectal neoplasia sufficiently to permit the lengthening of surveillance intervals in most patients and to clarify important issues regarding the mechanisms of colorectal carcinogenesis and chemoprevention.

Condition	Intervention	Phase
Colorectal Cancer Polyps Adenomas	Drug: Calcium Carbonate  Drug: Vitamin D3	Phase II Phase III

Further Study Details: 

Primary Outcomes: 1. Supplementation with vitamin D3 (1000 IU/day) reduces the risk of new adenomas in patients with a recent history of these tumors.; 2. Supplementation with calcium carbonate (1200 mg elemental calcium/day) reduces the risk of new adenomas; 3. Supplementation with both vitamin D3 (1000 IU/day) and calcium carbonate (1200 mg elemental calcium/day) reduces the risk of new adenomas more than supplementation with calcium carbonate alone.
Secondary Outcomes: 1. Supplementation with both vitamin D3 and calcium carbonate reduces the risk of new adenomas more than supplementation with vitamin D3 alone.; 2.Supplementation with vitamin D3 will have a greater effect among individuals whose initial serum 25-OH vitamin D level is less than the overall median, compared with subjects whose levels are greater than the median.; 3.The effects of calcium and vitamin D on adenoma occurrence will be more marked for adenomas with advanced histology (>25% villous features, advanced dysplasia) than for tubular adenomas.; 4. The effect of supplementation with vitamin D3 will be modified by polymorphisms at the 3'''' end of the vitamin D receptor gene.
Expected Total Enrollment:  2000

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 10 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 modified 2 x 2 factorial design to vitamin D (1000 IU/day), calcium carbonate (1200 mg elemental calcium/day), both agents, or placebo only. Women who decline to forego calcium supplementation will be randomized only to calcium alone or to calcium plus vitamin D. 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. Participants will agree to avoid taking study agents outside the trial and will initially be observed in a 3-month placebo run-in period to identify (and exclude before randomization) subjects likely not to adhere to the study regimen. We anticipate enrolling about 2500 participants to reach a total of approximately 2000 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 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 neoplastic polyps 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 placebo (with or without calcium), between subjects randomized to calcium (with or without vitamin D) versus those randomized to placebo (with or without vitamin D, excluding women electing to receive calcium and 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 effect of calcium plus vitamin D versus vitamin D alone, and the impact of baseline vitamin D levels and VDR polymorphisms on the vitamin D effects. Effects on advanced adenomas will also be assessed.

Ages Eligible for Study:  45 Years   -   75 Years,  Genders Eligible for Study:  Both

Criteria

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. COPD 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 HCV RNA

Drug exclusions:

• Use of chronic oral cortico-steroid 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

Please refer to this study by ClinicalTrials.gov identifier  NCT00153816

John A Baron, MD, MSc.      603-650-3456    john.a.baron@dartmouth.edu
Elizabeth L. Barry, PhD      603-650-3475    Elizabeth.L.Barry@dartmouth.edu

California
      University of Southern California, Los Angeles,  California,  90089,  United States; Recruiting
Colorado
      University of Colorado, Denver,  Colorado,  80220,  United States; Recruiting
Georgia
      Emory University, Atlanta,  Georgia,  30322,  United States; Recruiting
Iowa
      University of Iowa, Iowa City,  Iowa,  52242,  United States; Recruiting
Minnesota
      University of Minnesota, Minneapolis,  Minnesota,  55455,  United States; Recruiting
New Hampshire
      Dartmouth Hitchcock Medical Center, Lebanon,  New Hampshire,  03766,  United States; Recruiting
North Carolina
      University of North Carolina, Chapel Hill,  North Carolina,  27599,  United States; Recruiting
Ohio
      Cleveland Clinic Foundation, Cleveland,  Ohio,  44195,  United States; Recruiting
South Carolina
      University of South Carolina, Columbia,  South Carolina,  29203,  United States; Recruiting
Texas
      University of Texas, Houston,  Texas,  77030,  United States; Recruiting

Study chairs or principal investigators

John A. Baron, MD,  Principal Investigator,  Dartmouth Medical School   

Study ID Numbers:  16489
Last Updated:  September 9, 2005
Record first received:  September 7, 2005
ClinicalTrials.gov Identifier:  NCT00153816
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-09-13