Calcium and Vitamin D vs Markers of Adenomatous Polyps

Study Overview
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Brief Summary
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The purpose of this study is to test whether calcium and/or vitamin D supplementation favorably affects a set of biomarkers of risk for colon cancer in persons who are at higher than average risk for colon cancer (ie, have already undergone the removal of adenomatous polyps, which are known to be precursors to developing colon cancer).

Detailed Description
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There is strong biologic plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans (yet the previously reported observational evidence, although generally supportive, is inconsistent), and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, other than a possible reduction of colorectal epithelial cell proliferation by calcium, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer other than the possible exception of proliferation markers that, at best, have limited usefulness as individual markers. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways (APC, MSH2, MLH1), and 3) a more complete picture of the cell cycle events in colorectal epithelial crypt cells (short and long-term proliferation: MIB-1 and telomerase; differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax, and bak) that has not yet been tested in a chemoprevention trial. To address these needs, we will conduct a preliminary, randomized, double-blind, placebo-controlled, 2 x 2 factorial chemoprevention trial (n = 88) of calcium 2,000 mg/day and vitamin D3 800 IU/day, alone and in combination vs placebo over 6 months in patients with recent removal of sporadic adenomatous colorectal polyps, to investigate their effects on the individual components and aggregate profile of our colorectal cancer risk biomarker panel. We will also examine study results stratified by NSAID use and Bsm I vitamin D receptor genotypes. The preliminary estimates of treatment effect sizes and variabilities will be used to refine the biomarker panel and study design and to calculate the needed sample size for a potential full-scale study. We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of exploring the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, on the modulation of a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia.

Official Title
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Calcium, Vitamin D, and Colon Cancer Risk Biomarkers

Conditions
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Colorectal Adenomatous Polyps

Intervention / Treatment
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* Dietary Supplement: Calcium and vitamin D3 combined
* Drug: Placebo
* Dietary Supplement: Calcium
* Dietary Supplement: Vitamin D3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age 30-74 adenomatous colon polyp within past 3 years general good health with life expectancy of at least 2 years available for 8 months and able to come for clinic visits Exclusion Criteria: cancer within 5 years active major disease renal impairment history of kidney stones significant dietary change or weight loss within past 6 months unable to forego usual calcium or vitamin D use during study

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calcium<br>Calcium 2,000 mg/day as calcium carbonate in two divided doses with food | Dietary Supplement: Calcium<br>* Calcium 2,000 mg/day as calcium carbonate in two divided doses with meals over 6 months<br>|
| Experimental: Vitamin D3<br>Vitamin D3 800 IU given as 400 IU twice daily with food over 6 months | Dietary Supplement: Vitamin D3<br>* Vitamin D3 800 IU given as 400 IU twice daily with food over 6 months<br>|
| Experimental: Calcium and vitamin D3 combined<br>Calcium 2,000 mg (as calcium carbonate) + vitamin D3 800 IU given in equal divided doses twice daily with meals over 6 months | Dietary Supplement: Calcium and vitamin D3 combined<br>* Calcium 2,000 mg (as calcium carbonate) + vitamin D3 800 IU given in equal divided doses twice daily with food over 6 months<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers of Risk for Colorectal Neoplasms | A panel of putative biomarkers of risk for colorectal neoplasms in biopsies of normal appearing rectal mucosa: COX-2, APC, MSH-2, MLH1, MIB-1, telomerase, p21, bcl-2, bax, bak, β-catenin, E-cadherin, TGFα, TGFβ1, calcium sensing receptor, vitamin D receptor, CYP27B1, CYP24, 8-OH-dG | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vitamin D metabolites | serum 25-OH-vitamin D3 and 1,25-OH-vitamin D3 | 6 months | 
| Circulating inflammation markers | serum CRP, TNF-α, IL-6, IL-1β, IL-8 and IL-10 | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colonic polyps, adenomatous polyps, colon cancer prevention, dietary supplements