Vitamin D and Fish Oil for Autoimmune Disease, Inflammation and Joint Pain

描述(由申请人提供)-我们建议利用NIH资助的一项新的大规模、随机、双盲、安慰剂对照的2x2因子试验，对维生素D(以维生素D3[胆钙化醇]的形式)和海洋omega-3脂肪酸(二十碳五烯酸[EPA]+二十二碳六烯酸[DHA])补充剂进行研究，以研究对自身免疫性疾病发病率、全身炎症的生物标志物和慢性膝部疼痛的影响。来自实验室研究、流行病学研究和小型预防试验的数据有力地表明，这些营养剂降低了自身免疫性疾病的风险，降低了循环中促炎症细胞因子的水平，并减轻了慢性关节疼痛。然而，从未在普通人群中进行过具有足够剂量的大型初级预防试验(即，未根据疾病风险进行选择)。人们对补充维生素D和鱼油的热情日益高涨，突显出迫切需要及时测试它们，以免它们的使用变得如此普遍，以至于不可能招募参与者和进行假设检验。这项由美国国立卫生研究院资助的VITAL随机对照试验即将开始，将涉及从120万人的邮件中招募的20,000名年龄为60岁的男性和年龄为65岁的女性，其中包括美国退休人员协会(AARP)(前身为美国退休人员协会)的成员和其他人。这封邮件将包含一封描述试验的信，一份知情同意书，以及一份关于过去病史的问卷，包括自身免疫性疾病和慢性膝关节疼痛的筛查评估，以及饮食、药物和营养补充剂的使用。在3个月的安慰剂试验结束时，那些仍然愿意和符合条件的人，以及那些报告至少服用了三分之二的药片的人，将被随机分配到四个治疗组中的一个，为期5年：维生素D3(1600IU/d)和鱼油(EPA+DHA，1g/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和安慰剂鱼油。每隔一年，参与者将收到新的药片供应，以及对发生的自身免疫性疾病、膝盖疼痛、依从性和潜在副作用的评估。医生终点委员会将通过医疗记录审查确认所有自身免疫性疾病终点。我们预计将对600例自身免疫性疾病的发病病例进行验证，这将使我们有足够的统计能力来评估补充剂对疾病发病率的影响。基线和随访中的血液样本将从2000人的随机亚队列中收集，并分析全身炎症的生物标记物的变化：C-反应蛋白、白细胞介素6和肿瘤坏死因子-a。大约2000名患有慢性、频繁膝部疼痛的患者将接受年度问卷调查，这将为评估补充剂对慢性膝部疼痛的效果提供充足的统计力量。为了完成膝关节疼痛的随机化前评估，这项辅助研究必须与2010年1月开始的Parent VITAL试验的登记同步进行，这一点至关重要。鉴于NIH资助的VITAL试验以及我们在之前的大型邮寄试验和队列研究中的成功，拟议的试验将提供关于中心研究假设的决定性的积极或信息性的无效结果。

DESCRIPTION (provided by applicant): - We propose to leverage a newly NIH-funded large, randomized, double-blind, placebo-controlled, 2x2 factorial trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements to study effects upon autoimmune disease incidence, biomarkers of systemic inflammation, and chronic knee pain. Data from laboratory studies, epidemiologic research, and small prevention trials strongly suggest that these nutritional agents reduce the risk of autoimmune diseases, reduce levels of circulating pro-inflammatory cytokines, and decrease chronic joint pain. However, large primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) have never been conducted. The growing enthusiasm for supplemental vitamin D and fish oils underscores the urgent need for their timely testing, before their use becomes so prevalent as to render participant recruitment and hypothesis testing impossible. The NIH-funded VITAL randomized controlled trial about to begin will involve 20,000 men aged e60 and women aged e65 recruited from a mailing to 1.2 million persons, including members of AARP (formerly known as the American Association of Retired Persons), and others. The mailing will contain a letter describing the trial, an informed consent form, and a questionnaire about past medical history, including autoimmune diseases and a screening assessment of chronic knee pain, as well as diet, medication and nutritional supplement use. At the end of a 3 month placebo run-in, those who remain willing and eligible, and who report having taken at least two-thirds of the pills, will be randomly assigned to one of four treatment groups for 5 years: vitamin D3 (1600 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 yearly intervals, participants will receive a new supply of pills, and assessments of incident autoimmune diseases, knee pain, compliance and potential side effects. A physician endpoints committee will confirm all autoimmune disease endpoints by medical record review. We anticipate validation of 600 incident cases of autoimmune disease, giving us sufficient statistical power to assess supplement effects on disease incidence. Blood samples at baseline and in follow-up will be collected in a random subcohort of 2000 individuals and analyzed for changes in biomarkers of systemic inflammation: C-reactive protein, interleukin-6, and tumor necrosis factor-a. Approximately 2000 individuals with chronic, frequent knee pain will be followed with annual questionnaires, providing ample statistical power to evaluate the supplement effects upon chronic knee pain. To complete the pre-randomization assessment of knee pain, it is critically important that this ancillary study be undertaken in parallel to enrollment for the parent VITAL trial, beginning January 2010. Given the NIH-funded VITAL trial and our success with prior large mail-based trials and cohort studies, the proposed trial will furnish either definitive positive or informative null results regarding the central study hypotheses.