In this application we propose to complete CA098286, a double-blind, randomized, controlled trial of supplementation with vitamin D and/or calcium for the prevention of colorectal adenomas. The study builds on extensive epidemiological and experimental data indicating that both vitamin D and calcium have anti-neoplastic effects in the large bowel and that these agents interact, each requiring the other for full effect. Despite the strong supporting data, randomized trials are needed to confirm the purported efficacy of vitamin D, clarify its persistence, and assess the possible interaction with calcium. Experience with previous candidate chemopreventive agents for large bowel neoplasia shows that observation of a single colonoscopic surveillance cycle provides an incomplete evaluation of efficacy. Some agents have shown maximal effects only with longer follow-up;others have shown "rebound" increases in adenoma risk after treatment ends. Eligible subjects for the trial had a recent adenoma and no known polyps remaining in the large bowel. A total of 2259 subjects have been randomized to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. Women were offered the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up is either 3 years or 5 years after the qualifying exam, as planned by each subject's gastroenterologist. The main endpoint of the study is one or more neoplastic polyps of the bowel on follow-up;advanced lesions and multiple lesions are secondary endpoints. After completion of study treatment, subjects are followed for one subsequent colonoscopic surveillance cycle. The study has successfully met its milestones during the first 10 years of funding. Enrollment proceeded according to schedule and subjects have shown very good compliance with study procedures and agents. Recruitment into the post-treatment follow-up has been excellent. We now request funds for the final phases of the study: completion of treatment for a few subjects, post- treatment follow-up, and analyses of on-treatment and post-treatment adenoma occurrence. In our main analyses, we will assess the effect of vitamin D alone vs. placebo and that of vitamin D + calcium vs. calcium alone and also test whether there is a "rebound" in adenoma risk after cessation of vitamin D treatment. Under conservative assumptions, we will have greater than 95% power to detect a 20% reduction in adenoma recurrence with vitamin D vs. placebo, 89% power to detect a 25% reduction with calcium plus vitamin D vs. calcium alone and 80% power to reject a non-inferiority hypothesis regarding vitamin D vs. placebo, with an inferiority margin of 0.065 during post-treatment follow-up. Our secondary analyses will address advanced and multiple lesions, the interaction of calcium and vitamin D, and the modifying effects of baseline 25-OH vitamin D levels and polymorphisms in the vitamin D receptor on vitamin D treatment effects.

Public Health Relevance

Colorectal cancer is one of the most common cancers in the U.S. This study aims to confirm in a clinical trial that supplementation with calcium or vitamin D can reduce the risk of colorectal adenomas, benign tumors that can evolve into cancer if left in place. The study agents are safe, so if they are effective in interfering with carcinogenesis in th large bowel, they could have a substantial beneficial effect on public health.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098286-11
Application #
8439210
Study Section
Special Emphasis Panel (ZCA1-GRB-T (O1))
Program Officer
Umar, Asad
Project Start
2002-12-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$2,871,949
Indirect Cost
$254,955
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Liu, Siyu; Barry, Elizabeth L; Baron, John A et al. (2016) Effects of supplemental calcium and vitamin D on the APC/β-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients. Mol Carcinog :
Rees, Judy R; Mott, Leila A; Barry, Elizabeth L et al. (2016) Randomized controlled trials: who fails run-in? Trials 17:374
Barry, Elizabeth L; Peacock, Janet L; Rees, Judy R et al. (2016) Vitamin D Receptor Genotype, Vitamin D3 Supplementation, and Risk of Colorectal Adenomas: A Randomized Clinical Trial. JAMA Oncol :
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
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
Peery, Anne F; Sandler, Robert S; Galanko, Joseph A et al. (2015) Risk Factors for Hemorrhoids on Screening Colonoscopy. PLoS One 10:e0139100
Crockett, Seth D; Mott, Leila A; Barry, Elizabeth L et al. (2014) C-reactive protein and risk of colorectal adenomas or serrated polyps: a prospective study. Cancer Prev Res (Phila) 7:1122-7
Barry, Elizabeth L; Rees, Judy R; Peacock, Janet L et al. (2014) Genetic variants in CYP2R1, CYP24A1, and VDR modify the efficacy of vitamin D3 supplementation for increasing serum 25-hydroxyvitamin D levels in a randomized controlled trial. J Clin Endocrinol Metab 99:E2133-7
Barry, Elizabeth L; Mott, Leila A; Melamed, Michal L et al. (2014) Calcium supplementation increases blood creatinine concentration in a randomized controlled trial. PLoS One 9:e108094
Peery, Anne F; Baron, John A (2014) Reply: To PMID 23891924. Clin Gastroenterol Hepatol 12:1201-2

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