Impact of Icosapent Ethyl on Alzheimers Disease Biomarkers in Preclinical Adults

 描述(由申请人提供)： 超过500万美国人患有阿尔茨海默病(AD)，除非找到有效的预防策略，否则这一数字预计到2050年将增加两倍。退伍军人患AD的风险甚至比普通人群更高，这可能是因为他们更多地暴露在加速AD病理的因素中，包括血管风险因素、创伤性脑损伤和创伤后应激障碍。AD病理发生在认知症状出现前几十年，其特征是与记忆和学习相关的大脑区域的淀粉样斑块、神经原纤维缠结和局部脑血流减少。虽然脑动脉功能障碍在AD病理发展的早期和症状开始前几十年就会发生，但治疗这种早期脑血管功能障碍的效果却鲜为人知。Omega-3脂肪酸二十碳五烯酸可以改善动脉功能和脑血流，减轻与β-淀粉样蛋白相关的不良大脑变化，并改善动物的认知-这些变化都可以潜在地预防AD。然而，目前还不清楚EPA是否有益于影响认知健康的成年人的这些过程或认知表现，这些成年人患AD的风险增加。2012年，美国食品和药物管理局批准了第一种治疗高甘油三酯血症的大剂量处方EPA药物，名为二十碳五烯酸乙酯(在美国以Vascepa(R)的形式出售)。该制剂使用方便，安全性好，是预防阿尔茨海默病的理想制剂。这项拟议的研究是一项概念验证、随机、安慰剂对照、双盲、平行分组的临床试验，评估了20个月的二十碳联胺乙基疗法对150名认知健康的50-70岁退伍军人的磁共振成像、脑脊液和认知生物标记物的疗效，这些退伍军人因父母疾病史和载脂蛋白Eε4(ApoE 4)等位基因的增加而患上AD的风险增加。这项试验的主要目标是评估二十碳五烯酸乙酯是否有益地影响与阿尔茨海默病发病相关的中间生理指标，以便评估是否有必要进行更大规模、多地点、持续时间更长的阿尔茨海默氏症预防试验，以评估更明确的临床结果。假设：在父母有AD病史和APOE4患病率较高的中老年认知健康退伍军人中，20个月的治疗将有益于改善临床前AD生物标记物，包括局部脑血流、AD病理的脑脊液标记物和认知表现。具体目标1：研究服用20个月乙基每日4克与安慰剂相比18个月对临床前AD早期受累的预先定义的统计识别感兴趣区的动脉自旋标记磁共振局部脑血流量的影响；具体目标2：确定20个月乙基与安慰剂对临床前AD病理的脑脊液生物标志物(脑脊液β-淀粉样蛋白42、总tau和磷酸化tau181)的影响；具体目标3：在旨在评估临床前认知变化的综合测量--阿尔茨海默病合作研究(ADCS)临床前阿尔茨海默氏症认知复合体(PACC)上，评估20个月乙基苯丙胺与安慰剂的效果。如果20osapent乙基有益地改变高危退伍军人的AD生物标志物，拟议试验的结果将被用于开发多点、持续时间更长的临床试验，使用退伍军人管理局合作研究计划，以评估20osapent乙基不仅在AD生物标志物上的有效性，而且在更明确的临床结果上，如认知减退率和转化为轻度认知障碍(MCI)。如果未来的研究表明，二十碳五烯酸乙酯平均将阿尔茨海默病的发病时间推迟了5年，估计这将使阿尔茨海默病的发病率降低约50%。

 DESCRIPTION (provided by applicant): Over five million Americans have Alzheimer's disease (AD), and this number is expected to triple by 2050 unless effective preventive strategies are identified. Veterans are at an even higher risk for AD than the general population, possibly due to their increased exposure to factors that accelerate AD pathology, including vascular risk factors, traumatic brain injury, and post-traumatic stress disorder. AD pathology occurs decades before cognitive symptoms occur and is characterized by amyloid plaques, neurofibrillary tangles, and reduced regional cerebral blood flow in areas of the brain related to memory and learning. While cerebral arterial dysfunction occurs early in the development of AD pathology and decades before symptoms begin, the effects of treating such early vascular dysfunction in the brain are poorly understood. The omega-3 fatty acid eicosapentaenoic acid (EPA) improves arterial function and cerebral blood flow, attenuates adverse brain changes related to β-amyloid protein, and improves cognition in animals - changes that could all potentially protect against AD. However, it is not clear whether EPA beneficially affects these processes or cognitive performance in cognitively-healthy adults at increased risk for AD. In 2012, the Food and Drug Administration approved the first high-dose prescription EPA-only medication to treat hypertriglyceridemia, called icosapent ethyl (available as Vascepa(r) in the United States). This agent is readily available for use and has a good safety profile, making it a favorable agent to consider for AD prevention. The proposed study is a proof-of-concept, randomized, placebo-controlled, double-blind, parallel-group clinical trial assessing the efficacy of 18 months of icosapent ethyl therapy on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and cognitive biomarkers for AD in 150 cognitively-healthy Veterans ages 50-70 with increased risk for developing AD due to parental history of the disease and increased prevalence of apolipoprotein E ε4 (APOE4) allele. The overarching goal of this trial is to assess whether icosapent ethyl beneficially affects intermediate physiological measures associated with onset of AD in order to evaluate whether larger, multi-site, longer-duration Alzheimer's prevention trials are warranted to assess more definitive clinical outcomes. Hypothesis: In middle-aged and older cognitively-healthy Veterans with parental history of AD and high APOE4 prevalence, 18 months of treatment with icosapent ethyl will beneficially modify preclinical AD biomarkers, including regional cerebral blood flow, CSF markers of AD pathology, and cognitive performance. Specific Aim 1: To investigate the effects of 18 months of icosapent ethyl 4 g daily vs. placebo on arterial spin-labeling MRI regional cerebral blood flow in a pre-defined statistically-identified region of interest affected early in preclinical AD; Specific Aim 2: To determine the impact of 18 months of icosapent ethyl vs. placebo on CSF biomarkers of preclinical AD pathology (CSF β-amyloid- 42, total tau, and phosphorylated tau181); Specific Aim 3: To evaluate the effects of 18 months of icosapent ethyl vs. placebo on a composite measure designed to assess preclinical cognitive changes - the Alzheimer's Disease Cooperative Study (ADCS) Preclinical Alzheimer's Cognitive Composite (PACC). If icosapent ethyl beneficially modifies AD biomarkers in at-risk Veterans, the results from the proposed trial would be used to develop multi-site, longer-duration clinical trials using the VA Cooperative Studies Program to assess the efficacy of icosapent ethyl on not only AD biomarkers, but also on more clinically definitive outcomes, such as rate of cognitive decline and conversion to mild cognitive impairment (MCI). If future studies show that icosapent ethyl delays the onset of AD by even an average of 5 years, estimates suggest that this could reduce the prevalence of AD by about 50%.