Impact of Icosapent Ethyl on Alzheimers Disease Biomarkers in Preclinical Adults

二十碳五烯酸乙酯对临床前成人阿尔茨海默病生物标志物的影响

• 批准号: 10696935
• 负责人: CYNTHIA M CARLSSON
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696935
• 关键词: Adult; Affect; Age; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Animals; Antioxidants; Apolipoprotein E; Area; Attenuated; Biological Markers; Blood Vessels; Brain; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Cognition; Cognitive; Core-Binding Factor; Data; Development; Diagnosis; Disease; Docosahexaenoic Acids; Dose; Double-Blind Method; Eicosapentaenoic Acid; Endothelium; Exposure to; FDA approved; Feedback; Formulation; Functional disorder; Funding; Future; General Population; Goals; Health; Health Care Costs; Human; Hypertriglyceridemia; Impaired cognition; Incidence; Inflammation; LDL Cholesterol Lipoproteins; Lead; Learning; Letters; Lipids; Low-Density Lipoproteins; Magnetic Resonance Imaging; Maintenance; Measures; Memory; Mental Depression; Metabolism; Neurobehavioral Manifestations; Neurofibrillary Tangles; Neurons; Omega-3 Fatty Acids; Outcome; Participant; Pathogenesis; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Placebos; Population; Post-Traumatic Stress Disorders; Prevalence; Prevention; Prevention strategy; Prevention trial; Process; Quality of life; Randomized; Recording of previous events; Registries; Research Design; Risk; Safety; Senile Plaques; Site; Symptoms; Traumatic Brain Injury; United States; United States Food and Drug Administration; United States National Institutes of Health; Vascular Diseases; Veterans; Wisconsin; analytical method; arterial spin labeling; base; cognitive change; cognitive function; cognitive performance; cohort; cooperative study; design; effective therapy; efficacy evaluation; high risk; improved; interest; middle age; mild cognitive impairment; military service; neuroimaging; neuroprotection; novel; pre-clinical; preclinical study; prevent; primary endpoint; programs; public health relevance; secondary endpoint; tau Proteins; tau-1; vascular risk factor

 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%.

 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 的风险比普通人群更高，这可能是因为他们接触的因素增多。加速 AD 病理，包括血管危险因素、创伤性脑损伤和创伤后应激障碍，AD 病理在认知症状出现前数十年发生，其特征是淀粉样斑块、神经原纤维缠结和局部脑血流减少。虽然脑动脉功能障碍发生在 AD 病理发展的早期，并且在症状出现前几十年，但治疗这种早期大脑血管功能障碍的效果却知之甚少。 EPA）可以改善动脉功能和脑血流量，减轻与β-淀粉样蛋白相关的不良大脑变化，并改善动物的认知能力——这些变化都可能预防AD。然而，目前尚不清楚EPA是否有益。影响 AD 风险增加的认知健康成年人的这些过程或认知表现 2012 年，美国食品和药物管理局批准了第一种高剂量处方 EPA 药物来治疗高甘油三酯血症，称为二十碳五烯酸乙酯（商品名为 Vascepa(r)）。该药物易于使用且具有良好的安全性，使其成为预防 AD 的有利药物。拟议的研究是一项概念验证。随机、安慰剂对照、双盲、平行组临床试验，评估 150 名认知健康退伍军人接受 18 个月的二十碳五烯乙酯治疗对磁共振成像 (MRI)、脑脊液 (CSF) 和 AD 认知生物标志物的疗效50-70 岁的人由于父母的疾病史和载脂蛋白 E ε4 (APOE4) 等位基因的患病率增加而患 AD 的风险增加。该试验旨在评估二十碳五烯酸乙酯是否有益地影响与 AD 发病相关的中间生理指标，以评估是否需要进行更大规模、多部位、持续时间更长的阿尔茨海默病预防试验，以评估更明确的临床结果。假设：在中年。以及父母有 AD 病史且 APOE4 患病率较高、认知健康的老年退伍军人，二十碳五烯酸乙酯治疗 18 个月将有益地改变临床前 AD 生物标志物，包括局部脑血流量、 AD 病理学的 CSF 标记物和认知表现。 具体目标 1：研究 18 个月每日 4 g 二十碳五烯酸乙酯与安慰剂相比，对预先定义的特定区域的动脉自旋标记 MRI 局部脑血流的影响。临床前 AD 早期受影响的兴趣；具体目标 2：确定 18 个月的二十碳五烯酸乙酯与安慰剂对临床前 AD 病理学脑脊液生物标志物 (CSF) 的影响β-淀粉样蛋白 - 42、总 tau 和磷酸化 tau181）；具体目标 3：评估 18 个月的二十碳五烯酸乙酯与安慰剂对旨在评估临床前认知变化的综合指标的影响 - 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物 (PACC)。如果二十碳五烯酸乙酯有益地改变 AD 生物标志物。对于高危退伍军人来说，拟议试验的结果将用于开发多地点、持续时间较长的临床试验，利用 VA 合作研究计划来评估二十碳五烯乙酯不仅对 AD 生物标志物的功效，而且对更具有临床意义的确定性药物的功效如果未来的研究表明二十碳五烯酸乙酯可以将 AD 的发病时间平均延迟 5 年，那么估计表明这可以将 AD 的患病率降低 5 年。约50%。