The VITamin D and OmegA-3 TriaL (VITAL)

描述（由申请人提供）：这是维生素D和OmegA-3 TriaL（VITAL）的5年延续更新申请，该申请正在评估维生素D和海洋omega-3脂肪酸补充剂在癌症和心血管疾病（CVD）一级预防中的作用。这些药物在预防癌症、心血管疾病和其他疾病中的作用的证据在因果关系方面仍然没有定论，也不足以为一级预防提供营养建议。缺乏在一般人群中进行的适当设计的随机试验。为了填补这一知识空白，我们一直在进行VITAL，这是一项高度创新，具有成本效益，大规模，随机，双盲，安慰剂对照的临床试验，在26，000名美国男性和女性中基线时没有癌症或CVD，仅根据年龄（男性年龄为50岁，女性年龄为55岁）进行选择，黑人（ne 5000）。在2x2析因设计中，参与者被随机分配至维生素D3（胆钙化醇，2000 IU/d）和海洋ω-3脂肪酸（Omacor（R）鱼油，1 g/d，含有二十碳五烯酸[EPA] +二十二碳六烯酸[DHA]）补充剂（或安慰剂）。如果继续提供资金，中位治疗期将为5年。在第一个周期中，我们成功地达到或超过了我们的招募目标，招募了一个种族/民族多样化的队列，收集了超过16，000名参与者的基线血液/DNA样本（计划在6000名参与者中进行随访血液），并对试验中维生素D和omega-3脂肪酸测量的实验室测定进行了广泛的验证研究。年度随访问卷评估治疗依从性（通过参与者子集的血液样本确认），副作用，终点发生率以及癌症和血管风险因素。自我报告的终点由对治疗分配不知情的医生通过病历审查确认，死亡通过国家死亡指数和其他来源确定。我们存档的血液样本允许通过基线25-羟基维生素D和ω-3脂肪酸水平、生物标志物随时间的变化以及遗传/生化假设的测试来评估效应改变。与我们的科学同事一起，我们已经获得了18项辅助研究的资金，以评估这些补充剂在预防其他慢性疾病（包括糖尿病，认知能力下降，抑郁症和自身免疫性疾病）中的作用，并建立了一个临床组成部分，用于子队列的深入表型分析（n=1000）。预计该试验将为我们的主要研究提供明确的阳性或信息性无效结果。 该研究所将成为研究维生素D和欧米茄-3脂肪酸对健康影响的国家资源，并有机会进行广泛合作。这是一项高影响力的试验，因为这些发现可能对临床和公共卫生产生重大影响。

DESCRIPTION (provided by applicant): This is a renewal application for a 5-year continuation of the VITamin D and OmegA-3 TriaL (VITAL), which is evaluating the role of vitamin D and marine omega-3 fatty acid supplements in the primary prevention of cancer and cardiovascular disease (CVD). Evidence for a role of these agents in preventing cancer, CVD, and other diseases remains inconclusive regarding causality and insufficient to inform nutritional recommendations for primary prevention. Appropriately designed randomized trials in general populations are lacking. To fill this knowledge gap, we have been conducting VITAL, a highly innovative, cost-efficient, large-scale, randomized, double-blind, placebo-controlled clinical tria among 26,000 U.S. men and women without cancer or CVD at baseline, who have been selected only on age (men aged e50 and women aged e55), with an oversampling of blacks (ne5000). In a 2x2 factorial design, participants have been randomized to vitamin D3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (Omacor(R) fish oil, 1 g/d, containing eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements (or placebos) independently. Contingent on continued funding, the median treatment period will be 5 years. During the first cycle, we have successfully met or surpassed our recruitment goals, enrolled a racially/ethnically diverse cohort, collected baseline blood/DNA samples on >16,000 participants (with plans for follow-up bloods in 6000), and conducted extensive validation studies of the laboratory assays for vitamin D and omega-3 fatty acid measurements in the trial. Annual follow-up questionnaires assess treatment compliance (confirmed by blood samples in a subset of participants), side effects, endpoint occurrence, and cancer and vascular risk factors. Self-reported endpoints are confirmed by medical record review by physicians blinded to treatment assignment, and deaths are ascertained through the National Death Index-Plus and other sources. Our archived blood samples allow assessment of effect modification by baseline 25-hydroxyvitamin D and omega-3 fatty acid levels, changes in biomarkers over time, and testing of genetic/biochemical hypotheses. With our scientific colleagues, we have obtained funding for 18 ancillary studies to evaluate the role of these supplements in preventing other chronic diseases (including diabetes, cognitive decline, depression, and autoimmune disorders), and established an in-clinic component for in-depth phenotyping of a subcohort (n=1000). The trial is expected to provide either definitive positive or informative null results for our primary hypotheses and will serve as a national resource for research on the health effects of vitamin D and omega-3 fatty acids, with opportunities for extensive collaborations. This is a high-impact trial due to the potential for major clinical and public health implications of the findings.