Epidemiological and experimental data indicate that both vitamin D and calcium exert anti-neoplastic effects in the large bowel. However, evidence from clinical trials is required to clarify the synergistic and independent chemo preventive effects of these two agents. Neoplastic polyps (adenomas) of the bowel are recognized pre-malignant lesions and effective endpoints for chemoprevention studies. Our research consortium has successfully conducted several chemoprevention trials using these endpoints, and in this resubmission, we propose a multi-centered randomized, double blind, partial factorial trial of the efficacy of calcium carbonate and vitamin D in preventing the recurrence of neoplastic polyps of the large bowel. The study will involve 10 clinical centers in North America, a pathology center and a coordinating center. Each subject will have had at least one large bowel adenoma removed in the 4 months prior to study entry, with complete colonoscopic visualization of the colorectal mucosa and no known polyps remaining in the bowel. Participants will agree to avoid taking study agents outside the trial and will initially be observed in a 3- month placebo run-in period during which suitability for the study will be assessed. Suitable subjects will be randomized in a 2 x 2 factorial manner to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. Since many women may decline to forgo calcium supplementation, we will offer women the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up will occur at either 3 years or 5 years after the qualifying exam, as planned by each subject's physician. As safety measures, serum calcium, creatinine and 25-(OH) vitamin D levels will be obtained at baseline, and 1 year and 3 years after randomization. We anticipate enrolling about 2456 participants to reach a total of 1966 randomized subjects. Under conservative assumptions regarding event rates and study conduct, we will have greater than 89 percent power to detect a 20 percent reduction in adenoma recurrence with vitamin D versus placebo, and 85 percent power to detect a 25 percent reduction in recurrence with calcium plus vitamin D versus calcium alone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098286-02
Application #
6801919
Study Section
Subcommittee G - Education (NCI)
Program Officer
Malone, Winfred F
Project Start
2003-09-17
Project End
2008-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$3,454,069
Indirect Cost
Name
Dartmouth College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Hodge, Rebecca; Mandle, Hannah B; Ray, Stephen et al. (2018) Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKK?/? in the Normal Rectal Mucosa of Colorectal Adenoma Patients. Cancer Prev Res (Phila) 11:707-716
Crockett, Seth D; Barry, Elizabeth L; Mott, Leila A et al. (2018) Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial. Gut :
Anderson, Joseph C; Morris, Carolyn B; Robertson, Douglas J et al. (2018) Can the Sum of Adenoma Diameters (Adenoma Bulk) on Index Examination Predict Risk of Metachronous Advanced Neoplasia? J Clin Gastroenterol 52:628-634
Barry, Elizabeth L; Peacock, Janet L; Rees, Judy R et al. (2017) Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial. JAMA Oncol 3:628-635
Anderson, Joseph C; Baron, John A; Ahnen, Dennis J et al. (2017) Factors Associated With Shorter Colonoscopy Surveillance Intervals for Patients With Low-Risk Colorectal Adenomas and Effects on Outcome. Gastroenterology 152:1933-1943.e5
Liu, Siyu; Barry, Elizabeth L; Baron, John A et al. (2017) Effects of supplemental calcium and vitamin D on the APC/?-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients. Mol Carcinog 56:412-424
Rees, Judy R; Mott, Leila A; Barry, Elizabeth L et al. (2016) Randomized controlled trials: who fails run-in? Trials 17:374
Baron, John A; Barry, Elizabeth L; Mott, Leila A et al. (2015) A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. N Engl J Med 373:1519-30
Peery, Anne F; Sandler, Robert S; Galanko, Joseph A et al. (2015) Risk Factors for Hemorrhoids on Screening Colonoscopy. PLoS One 10:e0139100
Obuch, Joshua C; Pigott, Courtney M; Ahnen, Dennis J (2015) Sessile serrated polyps: detection, eradication, and prevention of the evil twin. Curr Treat Options Gastroenterol 13:156-70

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