Colorectal Chemoprevention with Calcium and Vitamin D

描述（由申请人提供）：本申请旨在更新CA 098286，这是一项补充维生素D和/或钙预防结直肠腺瘤的多中心、双盲、随机、安慰剂对照试验。这项研究建立在广泛的流行病学和实验数据的基础上，这些数据表明维生素D和钙在大肠中发挥抗肿瘤作用。该研究涉及美国的11个临床中心，一个病理中心和一个协调中心。每例受试者在进入研究前4个月内至少切除了一个大肠腺瘤，结肠镜下可以完整地看到结直肠粘膜，并且肠道中没有已知的息肉。排除存在研究药物毒性风险的受试者（例如，近期有肾结石病史），以及可能需要研究治疗的受试者（例如，骨质疏松症）。受试者同意避免在试验外服用研究药物。将合适的受试者以2 × 2析因方式随机分配至碳酸钙（1200 mg钙/天）、维生素D（1000 IU/天）、两种药剂或安慰剂。我们为女性提供随机选择，单独服用钙或钙加维生素D。结肠镜随访发生在资格考试后3年或5年，由每个受试者的胃肠病学家计划。作为安全性指标，将在基线和治疗期间获得血清钙、肌酐和25-（OH）维生素D水平。研究的主要终点是随访时出现一个或多个肿瘤性肠息肉;对晚期病变的影响评估将纳入次要分析。在关于事件发生率和研究进行的保守假设下，我们将有超过89%的把握度检测到维生素D与安慰剂相比腺瘤复发减少20%，并且有85%的把握度检测到钙+维生素D与单独钙相比复发减少25%。其他分析也将具有良好的统计功效。在资助的前5年，招生几乎完全按照计划进行;我们将在2007年11月30日达到或超过我们的目标招生。迄今为止，受试者对研究程序和药物的依从性极佳，很少有受试者因不良事件（如肾结石）或需要研究药物（如骨质疏松症）而不得不停止随机化治疗。我们现在申请资金，以完成所有2,200名随机受试者的计划治疗和随访，为首次疗效分析做准备，并实施治疗后随访。

DESCRIPTION (provided by applicant): This application is for the renewal of CA098286, a multicentered, double-blind, randomized, placebo 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 exert anti-neoplastic effects in the large bowel. The study involves 11 clinical centers in the US, a pathology center and a coordinating center. Each subject has 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. Subjects at risk for toxicity from study agents (e.g. with a recent history of kidney stones) are excluded, as are those with a likely need for the study treatments (e.g. with osteoporosis). Participants agree to avoid taking study agents outside the trial. Suitable subjects are randomized in a 2 x 2 factorial manner to calcium carbonate (1200 mg calcium/day), vitamin D (1000 IU/day), both agents, or placebo. We offer women the choice of being randomized to calcium alone or calcium plus vitamin D. Colonoscopic follow-up occurs at either 3 years or 5 years after the qualifying exam, as planned by each subject's gastroenterologist. As safety measures, serum calcium, creatinine and 25-(OH) vitamin D levels will be obtained at baseline, and during the treatment period. The main endpoint of the study is one or more neoplastic polyps of the bowel on followup; assessment of effects for advanced lesions will be included in secondary analyses. Under conservative assumptions regarding event rates and study conduct, we will have greater than 89% power to detect a 20% reduction in adenoma recurrence with vitamin D versus placebo, and 85% power to detect a 25% reduction in recurrence with calcium plus vitamin D versus calcium alone. Other analyses will also have good statistical power. During the first 5 years of funding, enrollment has proceeded almost exactly according to schedule; we will meet or exceed our target enrollment on November 30, 2007. To date, subjects have shown excellent compliance with study procedures and agents, and few subjects have had to stop randomized treatment because of adverse events (e.g. kidney stones) or a need for the study agents (e.g. osteoporosis). We now request funds to complete the planned treatment and follow-up for all 2,200 randomized subjects, prepare for the first efficacy analyses, and implement a post-treatment follow-up.