A Large Randomized Trial of Vitamin D, Omega-3 Fatty Acids and Cognitive Decline

描述（由申请人提供）：VITAL（维生素D和OmegA-3试验）研究最近获得资助（招募开始于2010年1月），以调查维生素D和海洋OmegA-3脂肪酸补充剂对心血管疾病和癌症一级预防的影响。我们建议在3000名65岁以上的参与者中启动一项认知衰退的子研究（VITAL-Cog），其中包括1000名非洲裔美国人。这是一个令人兴奋的机会，可以开展一项大规模、高成本效益的随机双盲安慰剂对照2 × 2因子试验，研究维生素D（维生素D3[胆钙化醇]，2000 IU/天）和海洋omega-3脂肪酸（二十二碳六烯酸+二十碳五烯酸，1000 mg/天）补充剂，以减缓认知能力下降。来自实验室研究、流行病学研究、小型一级预防试验和/或大型二级预防试验的数据表明，这些营养制剂可能会减少认知能力下降，但缺乏在普遍健康的老年人群中进行的大型试验。公众对补充维生素D和鱼油的热情日益高涨，这凸显了在它们的使用（通过补充剂和食品强化）变得足够普遍之前，及时启动这样一项试验的迫切需要。VITAL参与者将通过邮件从健康和其他专业人士、美国退休人员协会（AARP）成员、Essence杂志订阅者等人群中招募；非裔美国人将被过度抽样，因为他们维生素D缺乏症的患病率更高。受访者将参加为期3个月的安慰剂磨合阶段，以测试参与情况。我们建议在磨合期进行基线电话认知测试，允许进行预随机化评估。电话认知测试将包括一般认知、言语记忆和执行功能7项测试（我们在电话认知测试方面有丰富的经验，该测试将在300名VITAL-Cog参与者中进行面对面的认知测试）。在试验结束时，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4.5年。将收集血液样本，以评估基线25-羟基维生素D， omega-3脂肪酸水平以及载脂蛋白E4状态的效果改变。每隔1年，参与者将收到一份新的药丸供应和一份关于依从性、可能的副作用和病史的随访问卷。每隔1.5 - 2年，VITAL-cog参与者将接受随访认知功能评估，在4.5年期间共进行3次评估；衰退最严重的第10百分位的参与者也将接受使用痴呆问卷的电话采访。鉴于我们之前在多个试验环境中基于电话的认知功能评估的成功，我们相信VITAL-cog将能够为研究假设提供明确的结果。为了完成认知功能的预随机化评估，至关重要的是，VITAL-Cog必须与本试验（1 U01 CA138962）的安慰剂磨合期同时进行，该试验计划于2010年4月开始。

DESCRIPTION (provided by applicant): The VITAL (VITamin D and OmegA-3 TriaL) study was recently funded (recruitment starts January 2010) to investigate the effects of vitamin D and marine omega-3 fatty acid supplements on the primary prevention of cardiovascular disease and cancer. We propose to initiate a substudy of cognitive decline (VITAL-Cog) among 3000 participants aged 65+years, including 1000 African-Americans. This is an exciting opportunity to conduct a large and highly cost-effective randomized double-blind placebo-controlled 2x2 factorial trial of vitamin D (vitamin D3 [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (docosahexaenoic acid + eicosapentaenoic acid, 1000 mg/day) supplements for slowing cognitive decline. Data from laboratory studies, epidemiologic research, small primary prevention trials, and/or large secondary prevention trials suggest that these nutritional agents may reduce cognitive decline, but large trials among a generally healthy aging population are lacking. Growing public enthusiasm for supplemental vitamin D as well as fish oil underscores the urgent need for a timely initiation of such a trial, before their use becomes sufficiently prevalent (through supplements and food fortification). VITAL participants will be recruited from the general population by mail among health and other professionals, members of AARP, subscribers to Essence magazine, and others; African-Americans will be oversampled, as they have a higher prevalence of vitamin D deficiency. Respondents will be enrolled in a 3-month placebo run-in phase to test participation. We propose to administer baseline telephone cognitive testing during the run-in period, permitting a pre-randomization assessment. The telephone cognitive battery will include 7 tests of general cognition, verbal memory, and executive function (we have extensive experience with telephone cognitive testing, and the battery will be validated in 300 VITAL-Cog participants with in-person cognitive tests). At the end of the 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 4.5 years. Blood samples will be collected to allow assessment of effect modification by baseline 25-hydroxyvitamin D, omega-3 fatty acid levels, as well as by apolipoprotein E4 status. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects and medical history. At 1.5 to 2-year intervals, VITAL-cog participants will receive follow-up cognitive function assessments, for a total of 3 assessments over the 4.5 years; participants in the 10th percentile of worst decline will also receive telephone informant interviews using the Dementia Questionnaire. Given our success with prior telephone based cognitive function assessments in multiple trial settings, we believe VITAL-cog will be able to provide definitive results regarding the study hypotheses. To complete pre-randomization assessment of cognitive function, it is critical that VITAL-Cog be undertaken in parallel to the placebo run-in period for the parent trial (1 U01 CA138962), which is scheduled to begin in April 2010. PUBLIC HEALTH RELEVANCE: Given the projected aging of the population, maintaining cognitive function into older ages is of major public health importance, and early interventions may be most effective. The VITAL (VITamin D and OmegA-3 TriaL) study was recently funded and will begin recruitment in January 2010 to investigate the effects of vitamin D and marine omega-3 fatty acid supplements on heart health and cancer prevention. We propose an exciting substudy, incorporating cognitive testing among VITAL participants aged 65+ years to evaluate whether marine omega-3 fatty and vitamin D may be important in the maintenance of cognitive function in men and women.