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

摘要 这是一项延长维生素D干预后观察性随访5年的更新申请， OmegA-3 TriaL（VITAL），一项每日维生素D3（2000 IU）和 海洋ω-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）的初级预防中的作用， 25，871例≥50岁的美国男性和≥55岁的女性，包括5，106例非洲裔美国人。中位治疗为 5.3正在进行的2年干预后随访（加上数据关闭/分析）的资金将于5月31日结束， 2020. 5年的扩展期将产生中位干预后随访7年和中位累积 （干预+干预后）随访12年。在试验期间，虽然维生素D没有显着 降低整个队列中的总浸润性癌症发病率，有一个有希望的信号， 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 FA在总队列中没有减少主要CVD事件，但 心肌梗死（MI）和其他冠状动脉终点显著降低;亚组分析显示 在那些低基线鱼类摄入量和非裔美国人MI的主要CVD事件的减少。长 随访以解释潜伏期效应，并进行额外的研究以了解哪些人最有可能 获得净补充益处是必要的。年度调查将更新风险因素和终点 发生。报告的终点将通过医疗记录审查确认，并通过医疗保险进行补充 最大和无偏的终点捕获的连锁监测。死亡人数将通过国家统计局确定。 死亡指数加。存档的基线血液/DNA样本将允许检查试验的影响是否 癌症和心血管疾病的药物因（a）遗传因素（与维生素D相关的基因中的靶向变体）而异 代谢、吸收或受体功能或n-3 FA合成和激活;基于基因的祖先;遗传 风险评分）;（B）维生素K和镁状态;和（c）新的维生素D和n-3 FA生物标志物。此外，委员会认为， 持续的基础设施资助将提高正在进行的辅助研究的价值， 在预防其他疾病中的作用（迄今为止有23项资助研究，包括糖尿病、认知能力下降、骨 疾病和自身免疫性疾病），并允许未来的，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。基于VITAL的 优势-包括一个大型的，特征良好的，种族多样化的队列，在整个 试验;存档的血液样本;饮食和生活方式评估;以及严格裁定的终点-我们的 提案提供了一个极具创新性和成本效益的机会（直接成本<100美元/参与者/年） 进一步了解维生素D和n-3脂肪酸在人类健康和疾病中的作用。这是一个高- 由于研究结果可能对临床和公共卫生产生重大影响，因此需要进行影响研究。

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.