Colorectal Chemoprevention with Calcium and Vitamin D

产品说明：在本申请中，我们拟完成CA 098286，这是一项补充维生素D和/或钙预防结直肠腺瘤的双盲、随机、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和钙在大肠中具有抗肿瘤作用，并且这些药物相互作用，每种药物都需要另一种药物才能发挥全部作用。尽管有强大的支持 数据，需要随机试验来证实维生素D的功效，澄清其持久性，并评估与钙的可能相互作用。以往候选大肠肿瘤化学预防剂的经验表明，观察一个单一的结肠镜监测周期提供了一个不完整的疗效评价。一些药物只有在较长的随访期内才显示出最大的效果;另一些药物在治疗结束后显示出腺瘤风险的“反弹”增加。 符合试验条件的受试者最近有腺瘤，大肠中没有已知的息肉残留。共有2259例受试者被随机分配至碳酸钙（1200 mg钙/天）、维生素D（1000 IU/天）、两种药物或安慰剂组。妇女可以选择单独服用钙剂或钙剂加维生素D。结肠镜随访是资格考试后3年或5年，由每个受试者的胃肠病学家计划。研究的主要终点是随访时出现一个或多个肿瘤性肠息肉;晚期病变和多发性病变是次要终点。研究治疗完成后，对受试者进行一个后续结肠镜监测周期的随访。 这项研究在供资的头10年成功地达到了其里程碑。入组按照计划进行，受试者对研究程序和药物的依从性非常好。治疗后随访的招募情况非常好。 我们现在申请研究最后阶段的资金：完成少数受试者的治疗、治疗后随访以及治疗中和治疗后腺瘤发生率的分析。 在我们的主要分析中，我们将评估单独维生素D与安慰剂的效果，以及维生素D +钙与单独钙的效果，并测试停止维生素D治疗后腺瘤风险是否会“反弹”。在保守假设下，我们将有超过95%的把握度检测到维生素D与安慰剂相比腺瘤复发减少20%，89%的把握度检测到钙+维生素D与单用钙相比腺瘤复发减少25%，80%的把握度拒绝维生素D与安慰剂相比的非劣效性假设，治疗后随访期间的劣效性界值为0.065。我们的二次分析将涉及晚期和多发性病变、钙和维生素D的相互作用以及基线25-OH维生素D水平和维生素D受体多态性对维生素D治疗效果的修饰作用。

DESCRIPTION: 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.