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

描述（申请人提供）：- 我们建议利用一项新的NIH资助的大型，随机，双盲，安慰剂对照，维生素D的2x2析因试验（维生素D3 [胆钙化醇]的形式）和海洋欧米茄-3脂肪酸（二十碳五烯酸[EPA] +二十二碳六烯酸[DHA]）补充剂以研究对自身免疫性疾病发病率、全身性炎症的生物标志物、和慢性膝关节疼痛来自实验室研究、流行病学研究和小型预防试验的数据强烈表明，这些营养剂降低了自身免疫性疾病的风险，降低了循环促炎细胞因子的水平，并减少了慢性关节疼痛。然而，在一般人群中进行足够剂量的大型一级预防试验（即，疾病风险评估）从未进行过。人们对补充维生素D和鱼油的热情日益高涨，这突出表明迫切需要及时对其进行检测，以免其使用变得如此普遍，以至于无法招募参与者和进行假设检验。由NIH资助的VITAL随机对照试验即将开始，将涉及20，000名60岁的男性和65岁的女性，他们是通过邮寄招募到120万人中的，其中包括AARP（以前称为美国退休人员协会）的成员和其他人。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3个月的安慰剂导入期结束时，那些仍然愿意和合格的人，以及那些报告已经服用了至少三分之二的药丸的人，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和安慰剂鱼油。每隔一年，参与者将收到新的药丸供应，并评估事件的自身免疫性疾病，膝盖疼痛，依从性和潜在的副作用。医生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。我们预计将验证600例自身免疫性疾病的事件，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。将在2000名个体的随机子队列中收集基线和随访时的血液样本，并分析全身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。每年将对约2000名患有慢性、频繁膝关节疼痛的患者进行问卷调查，以提供充足的统计能力来评估补充剂对慢性膝关节疼痛的影响。为了完成膝关节疼痛的随机化前评估，从2010年1月开始，这项辅助研究与母试验VITAL的入组平行进行，这一点至关重要。鉴于NIH资助的VITAL试验以及我们在之前大型邮件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明确阳性或信息性无效结果。 公共卫生相关性：维生素D和海洋ω-3脂肪酸对预防自身免疫性疾病、减少炎症和缓解关节疼痛的健康益处在医学文献和大众媒体中受到越来越多的关注。然而，缺乏支持这两种容易获得的非处方药的这些健康益处的确切数据。这项大型随机临床试验的结果将阐明维生素D和海洋omega-3脂肪酸补充剂在预防自身免疫性疾病、对全身炎症生物标志物水平的影响以及老年男性和女性慢性膝关节疼痛的治疗中的作用。

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.