Effects of vitamin D and omega-3 fatty acids on infectious diseases and hCAP18

描述（由申请人提供）：感染是数百万美国老年人发病和死亡的主要原因。新兴的生物学和流行病学数据表明，维生素D补充剂和可能的海洋欧米茄-3脂肪酸（I-3 FA）具有抗菌功效。然而，在一般人群中进行的足够剂量的大型长期预防试验尚不可用。IOM最近呼吁对维生素D进行更多的研究。我们建议利用NIH资助的一项大型研究-维生素D和OmegA-3 TriaL（VITAL）-来检查维生素D和I-3 FA补充剂对感染的短期和长期影响。我们还将研究维生素D对血浆人抗菌肽（hCAP 18）水平的影响，这是维生素D假设的抗菌益处的潜在机制。VITAL是一项随机、双盲、安慰剂对照、2x2析因试验，有20，000名参与者（男性年龄60岁;女性年龄65岁）。从2011年4月开始并持续至2012年7月，受试者将入组3个月的导入期，在此期间他们将接受安慰剂。在导入期结束时，那些仍然愿意和合格的人，并且报告已经服用了至少三分之二的药丸，将被随机分配到四组之一，为期5年：维生素D3（2000 IU/d）和鱼油（EPA+DHA，1 g/d）;维生素D3和鱼油安慰剂;安慰剂维生素D3和鱼油;安慰剂维生素D3和安慰剂鱼油。每隔一年，参与者将收到一份新的药丸供应和一份关于依从性、可能的副作用和终点发生率的随访问卷。这项辅助研究的主要目的是解决上呼吸道感染（URI），并要求在2012年初及时创建一个子队列（10%样本，n= 2，000）。该URI子队列将在2012年2月/3月（基线）、2012年10月/11月和2013年2月/3月（同一季节，1年后）收到特殊邮件。后者的邮件将收集有关最近URI的详细信息（例如，严重程度、病程、治疗）。我们将采集基线和1年随访血液标本，以检测25（OH）D、I-3和hCAP 18水平的变化。这些数据将回答几个问题，包括维生素D是否增加hCAP 18水平，以及这种变化是否介导了URI的假设减少。次要目标将检查其他几种类型的感染（肺炎和流感，尿路感染，皮肤，任何抗菌剂治疗的感染，感染相关的住院/败血症），我们将通过CMS链接进行确认。在每种结局的250例病例子集中，我们将通过补充问卷进一步确认终点。长期随访将使我们能够解决新出现的问题，即早期的有益效果可能会随着长期补充而减弱甚至逆转。目前的研究提出了一种高效和创新的策略，以评估维生素D和I-3 FA补充剂对感染性疾病的短期和长期预防作用，并测试hCAP 18作为潜在机制。这些发现可能对预防老年人感染有直接的临床和公共卫生影响。 公共卫生相关性：维生素D和ω-3脂肪酸的健康益处在医学文献和大众媒体中越来越受到关注。然而，缺乏关于这些药物的健康益处和风险的确切数据。这项大型临床试验的结果将阐明维生素D和omega-3脂肪酸补充剂在预防男性和女性呼吸道感染和其他主要传染病方面的作用。

DESCRIPTION (provided by applicant): Infections are a leading cause of morbidity and mortality for millions of older Americans. Emerging biologic and epidemiologic data suggest antimicrobial benefits from vitamin D supplements, and possibly marine omega-3 fatty acids (I-3 FA). However, large, long-term prevention trials with adequate dosing in general populations are not available. The IOM recently called for more research on vitamin D. We propose to take advantage of a large NIH-funded study - the VITamin D and OmegA-3 TriaL (VITAL) - to examine the short- and long-term effects of vitamin D and I-3 FA supplements on infection. We also will examine the effect of vitamin D on plasma levels of human cathelicidin antimicrobial peptide (hCAP18), a potential mechanism for the hypothesized antimicrobial benefits of vitamin D. VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial with 20,000 participants (men age e60y; women e65y). Starting in April 2011 and continuing through July 2012, subjects will be enrolled in a 3-month run-in, during which they will receive placebos. At the end of the run-in, those who remain willing and eligible, and who report having taken at least two-thirds of pills, will be randomly assigned to one of four groups for 5 years: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d); vitamin D3 and fish oil placebo; placebo vitamin D3 and fish oil; and placebo vitamin D3 and placebo fish oil. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. Primary aims of this ancillary study will address upper respiratory infections (URIs) and require the timely creation of a subcohort (10% sample, n=2,000) in early 2012. This URI subcohort will receive special mailings in Feb/Mar 2012 (baseline), Oct/Nov 2012, and Feb/Mar 2013 (same season, 1 year later). The latter mailings will collect details about recent URIs (e.g., severity, duration of illness, treatments). We will collect baseline and 1-year follow-up blood specimens to test for changes in 25(OH)D, I-3, and hCAP18 levels. These data will answer several questions, including whether vitamin D increases hCAP18 levels, and whether this change mediates the hypothesized reduction in URIs. Secondary aims will examine several other types of infections (pneumonia & influenza, urinary tract infections, skin, any antimicrobial-treated infection, infection-related hospitalizations/sepsis), which we will confirm by CMS linkage. In a subset of 250 cases of each outcome, we will further confirm endpoints by supplemental questionnaire. Long-term follow-up will allow us to address the emerging concern that an early beneficial effect could be followed by a weakening or even reversal of benefit with prolonged supplementation. The current study presents a highly efficient and innovative strategy to evaluate vitamin D and I-3 FA supplementation for short- and long-term prevention of infectious diseases, and to test hCAP18 as a potential mechanism. The findings may have direct clinical and public health impact for the prevention of infections in older adults. PUBLIC HEALTH RELEVANCE: The purported health benefits of vitamin D and omega-3 fatty acids are receiving increasing attention in the medical literature and popular press. However, definitive data on the health benefits and risks of these agents are lacking. Findings from this large clinical trial will clarify the role of vitamin D and omega-3 fatty acid supplements in the prevention of respiratory infections and other major infectious diseases in men and women.