The VITamin D and OmegA-3 TriaL (VITAL): Post-Intervention Follow-Up

摘要 这是一项延长维生素D和维生素D干预后观察随访5年的续订申请 Omega-3试验(VITAL)，每日维生素D3(2000IU)的随机、安慰剂对照因子试验 海洋omega-3脂肪酸(n-3脂肪酸；1克Omacor®鱼油胶囊，含二十碳五烯酸[460 mg]+ 二十二碳六烯酸[380毫克])在癌症和心血管疾病(CVD)的一级预防中 25,871名年龄为≥50岁的美国男性和55岁的女性，其中包括5,106名非裔美国人。治疗中位数为 5.3年。正在进行的为期两年的干预后后续行动(加上数据结清/分析)的资金将于5月31日结束， 2020年。延长5年将产生中位数的干预后7年的随访和中位数的累积 (干预+干预后)随访12年。在试验期间，尽管维生素D没有显著地 降低总侵袭性癌症发病率在总体队列中，有一个令人振奋的信号，总的减少 癌症死亡率和亚组分析表明，非裔美国人和 体重指数正常。尽管n-3个FA并没有减少总队列中的主要心血管事件，但有 显著减少心肌梗死(MI)和其他冠状动脉终点；亚组分析显示 低基线鱼摄入量者的主要心血管事件减少，非裔美国人的MI减少。更长 跟进以说明潜伏期影响，并进行额外研究以了解哪些个人最有可能 获得净补充福利是有保证的。年度调查将更新风险因素和终点 发生了。报告的终端将通过医疗记录审查进行确认，并通过联邦医疗保险进行扩展 联动监测，最大限度地、无偏地捕获终端。死亡人数将通过国家 死亡指数-Plus。存档的基线血液/DNA样本将允许检查试验的效果 治疗癌症和心血管疾病的药物因以下因素而异：(A)遗传因素(与维生素D相关的基因的靶向变异 代谢、吸收或受体功能或n-3FA的合成和激活；基于基因的祖先；遗传 风险分数)；(B)维生素K和镁的状况；以及(C)新的维生素D和n-3FA生物标志物。此外， 持续的基础设施资金将提高正在进行的评估试验代理人的辅助研究的价值 在预防其他疾病方面的作用(迄今资助了23项研究，包括糖尿病、认知功能减退、骨骼 疾病和自身免疫疾病)，并允许未来的疾病，包括检查干预 对肿瘤分子标志物、DNA甲基化和基因表达的影响。在VITAL的基础上构建 优势-包括一个庞大的、特征良好的、种族多样化的队列，在整个 审判；存档的血液样本；饮食和生活方式评估；以及严格裁决的终点-我们的 建议书提供了一个极具创新性和成本效益的机会(直接成本为100美元/参与者/年) 增进对维生素D和n-3脂肪酸在人类健康和疾病中的作用的认识。这是一个很高的- 由于这一发现可能对临床和公共卫生产生重大影响，因此进行了影响研究。

ABSTRACT This is a renewal application to extend post-intervention observational follow-up for 5 yrs in the VITamin D and OmegA-3 TriaL (VITAL), a randomized, placebo-controlled factorial trial of daily vitamin D3 (2000 IU) and marine omega-3 fatty acids (n-3 FAs; 1-g Omacor® fish-oil capsule, with eicosapentaenoic acid [460 mg] + docosahexaenoic acid [380 mg]) in the primary prevention of cancer and cardiovascular disease (CVD) among 25,871 US men aged ≥50 and women aged ≥55 yrs, including 5,106 African Americans. Median treatment was 5.3 yrs. Funding for the ongoing 2-yr post-intervention follow-up (plus data closeout/analysis) ends on May 31, 2020. A 5-yr extension will yield a median post-intervention follow-up of 7 yrs and median cumulative (intervention + post-intervention) follow-up of 12 yrs. During the trial, although vitamin D did not significantly reduce total invasive cancer incidence in the overall cohort, there was a promising signal for a reduction in total cancer mortality, and subgroup analyses indicated cancer protection in African Americans and those with normal body mass index. Although n-3 FAs did not reduce major CVD events in the total cohort, there were significant reductions in myocardial infarction (MI) and other coronary endpoints; subgroup analyses showed reductions in major CVD events in those with low baseline fish intake and in MI in African Americans. Longer follow-up to account for latency effects and additional research to learn which individuals may be most likely to derive a net supplementation benefit is warranted. Annual surveys will update risk factors and endpoint occurrence. Reported endpoints will be confirmed by medical record review and augmented with Medicare linkage surveillance for maximal and unbiased endpoint capture. Deaths will be ascertained via the National Death Index-Plus. Archived baseline blood/DNA samples will allow examination of whether effects of the trial agents on cancer and CVD vary by (a) genetic factors (targeted variants in genes related to vitamin D metabolism, absorption, or receptor function or n-3 FA synthesis and activation; gene-based ancestry; genetic risk scores); (b) vitamin K and magnesium status; and (c) novel vitamin D and n-3 FA biomarkers. Moreover, continued infrastructure funding will enhance the value of ongoing ancillary studies evaluating the trial agents’ role in prevention of other diseases (23 funded studies to date, including diabetes, cognitive decline, bone disorders, and autoimmune conditions) and allow for future ones, including an examination of intervention effects on tumor molecular markers, DNA methylation, and gene expression. Building upon VITAL’s strengths—including a large, well-characterized, racially diverse cohort with high compliance throughout the trial; archived blood samples; dietary and lifestyle assessments; and rigorously adjudicated endpoints—our proposal offers an exceptionally innovative and cost-efficient (<$100/participant/yr in direct costs) opportunity to advance knowledge about the role of vitamin D and n-3 FAs in human health and disease. This is a high- impact study due to the potential for major clinical and public health implications of the findings.