Colorectal Chemoprevention with Calcium and Vitamin D

描述：在本申请中，我们建议完成CA098286，这是一项补充维生素D和/或钙以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，表明维生素D和钙在大肠中都有抗肿瘤作用，并且这些药物相互作用，相互需要对方才能充分发挥作用。尽管得到了强有力的支持 数据显示，需要进行随机试验来证实维生素D的所谓疗效，阐明其持久性，并评估其与钙的可能相互作用。以前的大肠肿瘤候选化学预防药物的经验表明，观察一个结肠镜检查周期提供的疗效评估是不完整的。一些药物只有在较长时间的随访中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一个腺瘤，大肠内没有已知的息肉残留。共有2259名受试者被随机分为碳酸钙(1200毫克钙/天)、维生素D(1000国际单位/天)、两种药物或安慰剂。女性被提供了两种选择，一种是随机接受单独补钙，另一种是补钙加维生素D。按照每个受试者的胃肠病专家的计划，结肠镜检查的随访时间是在合格检查后的3年或5年。研究的主要终点是随访时的一个或多个肠道肿瘤性息肉；晚期病变和多发性病变是次要终点。在完成研究治疗后，受试者被跟踪一个随后的结肠镜检查周期。这项研究在资助的头10年中成功地达到了其里程碑。招生工作按计划进行，受试者很好地遵守了学习程序和代理人的要求。招募到治疗后的后续工作一直很出色。我们现在要求为这项研究的最后阶段提供资金：完成对几个受试者的治疗，治疗后的随访，以及治疗中和治疗后腺瘤发生的分析。在我们的主要分析中，我们将评估单独服用维生素D与安慰剂的效果，以及维生素D+钙与单独服用钙的效果，并测试停止维生素D治疗后腺瘤风险是否出现“反弹”。在保守的假设下，我们将有超过95%的能力检测到服用维生素D与安慰剂相比腺瘤复发减少了20%，89%的能力检测到钙加维生素D与单独服用钙相比减少了25%，80%的能力拒绝了关于维生素D与安慰剂的非劣势假设，在治疗后的后续治疗中，劣势幅度为0.065。我们的二次分析将针对晚期和多发性病变，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受体多态对维生素D治疗效果的调节作用。

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.