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。新出现的生物学和流行病学数据表明，维生素D补充剂以及可能的海洋omega-3脂肪酸（i - 3fa）具有抗菌作用。然而，在一般人群中没有足够剂量的大型长期预防试验。美国国际医学研究院最近呼吁对维生素D进行更多的研究。我们建议利用美国国立卫生研究院资助的一项大型研究——维生素D和OmegA-3试验（VITAL）——来检验维生素D和I-3脂肪酸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（hCAP18）水平的影响，这是维生素D抗菌益处的潜在机制。VITAL是一项随机、双盲、安慰剂对照、2x2因子试验，有20,000名参与者（男性60岁，女性65岁）。从2011年4月开始，一直持续到2012年7月，受试者将参加为期3个月的磨合期，在此期间他们将获得安慰剂。在试验结束时，那些仍然愿意且符合条件的人，以及那些报告服用了至少三分之二药片的人，将被随机分配到四个组中的一个，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；以及安慰剂维生素D3和鱼油每隔1年，参与者将获得新的药物供应，并对依从性、可能的副作用和终点发生率进行随访问卷调查。这项辅助研究的主要目的是解决上呼吸道感染（uri）问题，并要求在2012年初及时创建一个亚队列（10%样本，n= 2000）。此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。后一种邮件将收集有关最近uri的详细信息（例如，严重程度、疾病持续时间、治疗）。我们将收集基线和1年随访血液标本，检测25(OH)D、I-3和hCAP18水平的变化。这些数据将回答几个问题，包括维生素D是否会增加hCAP18水平，以及这种变化是否会介导假设的uri减少。次要目的将检查几种其他类型的感染（肺炎和流感，尿路感染，皮肤，任何抗生素治疗感染，感染相关住院/败血症），我们将通过CMS链接确认。在每个结果的250例的子集中，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担忧，即早期的有益效果可能随着长期补充而减弱甚至逆转。本研究提出了一种高效和创新的策略来评估补充维生素D和I-3 FA对短期和长期预防传染病的作用，并测试hCAP18作为潜在的机制。研究结果可能对预防老年人感染有直接的临床和公共卫生影响。

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.