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资助的一项新的大型、随机、双盲、安慰剂对照、2x2因子试验，研究维生素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关节疼痛的影响。来自实验室研究、流行病学研究和小型预防试验的数据强烈表明，这些营养制剂可降低自身免疫性疾病的风险，降低循环促炎细胞因子的水平，并减轻慢性关节疼痛。然而，从未在一般人群（即未选择疾病风险人群）中进行过适当剂量的大型一级预防试验。对补充维生素D和鱼油的日益高涨的热情强调了对它们进行及时测试的迫切需要，以免它们的使用变得如此普遍，以至于无法进行参与者招募和假设测试。美国国立卫生研究院资助的VITAL随机对照试验即将开始，将从120万人的邮寄中招募2万名60岁的男性和65岁的女性，包括AARP（以前称为美国退休人员协会）的成员，以及其他。邮件将包含一封描述试验的信、一份知情同意书和一份关于既往病史的问卷，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。在为期3个月的安慰剂试验结束后，那些仍然愿意且符合条件并报告服用了至少三分之二药片的人，将被随机分配到四个治疗组中的一个，为期5年：维生素D3 （1600 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和鱼油每隔一年，参与者将获得新的药物供应，并评估自身免疫性疾病、膝关节疼痛、依从性和潜在副作用。医师终点委员会将通过病历审查确认所有自身免疫性疾病终点。我们预计将对600例自身免疫性疾病进行验证，这将为我们提供足够的统计能力来评估补充剂对疾病发病率的影响。基线和随访时的血液样本将在2000人的随机亚队列中收集，并分析全系统炎症生物标志物的变化：c反应蛋白、白细胞介素-6和肿瘤坏死因子-a。大约2000名慢性、频繁膝关节疼痛患者将进行年度问卷调查，为评估补充剂对慢性膝关节疼痛的影响提供充足的统计能力。为了完成膝关节疼痛的预随机化评估，至关重要的是，从2010年1月开始，这项辅助研究必须与父级VITAL试验的入组同时进行。考虑到美国国立卫生研究院资助的VITAL试验以及我们在之前的大型邮件试验和队列研究中取得的成功，拟议的试验将提供关于中心研究假设的明确阳性或信息性无效结果。

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. PUBLIC HEALTH RELEVANCE: The purported health benefits of vitamin D and marine omega-3 fatty acids for preventing autoimmune diseases, decreasing inflammation and relieving joint pain are receiving increasing attention in the medical literature and the popular press. However, definitive data supporting these health benefits of these two readily available over-the-counter agents are lacking. Findings from this large randomized clinical trial will clarify the roles of vitamin D and marine omega-3 fatty acid supplements for the prevention of autoimmune diseases, effects on levels of biomarkers of systemic inflammation, and treatment for chronic knee pain in older men and women.