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

描述（由申请人提供）：最近资助了VITAL（维生素D和OmegA-3 TriaL）研究（招募于2010年1月开始），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（包括1000名非洲裔美国人）中启动认知功能下降的子研究（VITAL-Cog）。这是一个令人兴奋的机会，可以进行一项关于维生素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）补充剂减缓认知能力下降的大型高成本效益随机双盲安慰剂对照2x2析因试验。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，这些营养剂可能会减少认知能力下降，但缺乏在总体健康的老龄化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，这突出表明迫切需要在它们的使用变得足够普遍（通过补充剂和食品强化）之前及时启动此类试验。VITAL的参与者将通过邮件从健康和其他专业人员、美国退休人员协会成员、《本质》杂志的订阅者和其他人中招募;非洲裔美国人将被过度抽样，因为他们有更高的维生素D缺乏症患病率。应答者将入组为期3个月的安慰剂导入期，以测试参与情况。我们建议在导入期进行基线电话认知测试，允许进行随机化前评估。电话认知成套测验将包括一般认知、非文字记忆和执行功能的7项测试（我们在电话认知测试方面拥有丰富的经验，该成套测验将在300名VITAL-Cog参与者中通过面对面认知测试进行验证）。在导入期结束时，那些仍然愿意和合格的人，以及那些报告服用了至少三分之二药丸的人，将被随机分配到四个治疗组中的一个，为期4.5年。将采集血液样本，以便通过基线25-羟基维生素D、omega-3脂肪酸水平以及载脂蛋白E4状态评估效应改变。每隔一年，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至2年，VITAL-cog参与者将接受随访认知功能评估，在4.5年内共进行3次评估;最严重下降的第10百分位参与者还将接受使用痴呆问卷的电话线人访谈。鉴于我们在多个试验环境中先前基于电话的认知功能评估的成功，我们相信VITAL-cog将能够提供关于研究假设的明确结果。为了完成认知功能的随机化前评估，VITAL-Cog与母试验（1 U 01 CA 138962）的安慰剂导入期平行进行至关重要，母试验计划于2010年4月开始。 公共卫生相关性：考虑到预计的人口老龄化，保持认知功能到老年是主要的公共卫生重要性，早期干预可能是最有效的。VITAL（维生素D和OmegA-3 TriaL）研究最近获得资助，并将于2010年1月开始招募，以调查维生素D和海洋omega-3脂肪酸补充剂对心脏健康和癌症预防的影响。我们提出了一项令人兴奋的子研究，在65岁以上的VITAL参与者中进行认知测试，以评估海洋omega-3脂肪酸和维生素D是否对维持男性和女性的认知功能很重要。

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.