Calcium and Vitamin D vs Markers of Adenomatous Polyps

Colorectal Adenomatous Polyps Clinical Trial

— CaDvMAP  

Official title:

Calcium, Vitamin D, and Colon Cancer Risk Biomarkers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00208793
• Other study ID #: 0126-2004
• Secondary ID: R01CA104637
• Status: Completed
• Phase: Phase 2
• First received: September 13, 2005
• Last updated: November 22, 2013
• Start date: May 2005
• Est. completion date: February 2013

Study information

• Verified date: November 2013
• Source: Emory University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: February 2013
• Est. primary completion date: September 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 74 Years

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

• Adenomatous Polyps
• Colorectal Adenomatous Polyps
• Polyps

Intervention

Dietary Supplement:
• Calcium and vitamin D3 combined
Calcium 2,000 mg (as calcium carbonate) + vitamin D3 800 IU given in equal divided doses twice daily with food over 6 months

Drug:
• Placebo
Placebo

Dietary Supplement:
• Calcium
Calcium 2,000 mg/day as calcium carbonate in two divided doses with meals over 6 months
• Vitamin D3
Vitamin D3 800 IU given as 400 IU twice daily with food over 6 months

Locations

Country	Name	City	State
United States	The Emory Clinic, Division of Digestive Diseases	Atlanta	Georgia

Sponsors (3)

Lead Sponsor	Collaborator
Emory University	National Cancer Institute (NCI), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (10)

Ahearn TU, McCullough ML, Flanders WD, Long Q, Sidelnikov E, Fedirko V, Daniel CR, Rutherford RE, Shaukat A, Bostick RM. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of c — View Citation

Ahearn TU, Shaukat A, Flanders WD, Rutherford RE, Bostick RM. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/ß-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prev Res (Phila). 2012 — View Citation

Chai W, Bostick RM, Ahearn TU, Franke AA, Custer LJ, Cooney RV. Effects of vitamin D3 and calcium supplementation on serum levels of tocopherols, retinol, and specific vitamin D metabolites. Nutr Cancer. 2012;64(1):57-64. doi: 10.1080/01635581.2012.630552 — View Citation

Fedirko V, Bostick RM, Flanders WD, Long Q, Shaukat A, Rutherford RE, Daniel CR, Cohen V, Dash C. Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: a randomized, double-blind, placebo-controlled clinical tria — View Citation

Fedirko V, Bostick RM, Flanders WD, Long Q, Sidelnikov E, Shaukat A, Daniel CR, Rutherford RE, Woodard JJ. Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial. Cancer Epidemiol Biomarke — View Citation

Fedirko V, Bostick RM, Long Q, Flanders WD, McCullough ML, Sidelnikov E, Daniel CR, Rutherford RE, Shaukat A. Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial. Cancer Epi — View Citation

Hopkins MH, Flanders WD, Bostick RM. Associations of circulating inflammatory biomarkers with risk factors for colorectal cancer in colorectal adenoma patients. Biomark Insights. 2012;7:143-50. doi: 10.4137/BMI.S10092. Epub 2012 Nov 5. — View Citation

Hopkins MH, Owen J, Ahearn T, Fedirko V, Flanders WD, Jones DP, Bostick RM. Effects of supplemental vitamin D and calcium on biomarkers of inflammation in colorectal adenoma patients: a randomized, controlled clinical trial. Cancer Prev Res (Phila). 2011 — View Citation

McCullough ML, Bostick RM, Daniel CR, Flanders WD, Shaukat A, Davison J, Rangaswamy U, Hollis BW. Vitamin D status and impact of vitamin D3 and/or calcium supplementation in a randomized pilot study in the Southeastern United States. J Am Coll Nutr. 2009 — View Citation

Sidelnikov E, Bostick RM, Flanders WD, Long Q, Fedirko V, Shaukat A, Daniel CR, Rutherford RE. Effects of calcium and vitamin D on MLH1 and MSH2 expression in rectal mucosa of sporadic colorectal adenoma patients. Cancer Epidemiol Biomarkers Prev. 2010 Ap — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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, ß-catenin, E-cadherin, TGFa, TGFß1, calcium sensing receptor, vitamin D receptor, CYP27B1, CYP24, 8-OH-dG	6 months	No
Secondary	Vitamin D metabolites	serum 25-OH-vitamin D3 and 1,25-OH-vitamin D3	6 months	No
Secondary	Circulating inflammation markers	serum CRP, TNF-a, IL-6, IL-1ß, IL-8 and IL-10	6 months	No