阿尔茨海默病临床试验中安慰剂组报告的 APOE-ε4 等位基因相关不良事件:对抗淀粉样 beta 疗法的影响

Kenichiro Sato, Yoshiki Niimi, R. Ihara, Kazushi Suzuki, Atsushi Iwata, Takeshi Iwatsubo
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引用次数: 0

摘要

APOE-ε4等位基因是阿尔茨海默病(AD)和淀粉样蛋白相关成像异常(ARIA)抗淀粉样蛋白β疗法的风险因素,也与高脂血症或动脉粥样硬化等脑血管风险因素有关。在AD临床试验期间,APOE-ε4携带者可能会出现与这些风险相关的神经精神不良事件(AEs),这使得根据症状区分ARIA和脑血管事件变得更加复杂。本研究旨在探讨在 AD 临床试验中考虑 APOE-ε4 等位基因对非 ARIA AEs 风险的假设影响。我们使用了来自阿尔茨海默病关键路径(CPAD)的数据,这些数据来自AD治疗随机对照试验(RCT)的安慰剂组。我们确定了 APOE-ε4 携带者是否更频繁地报告 AEs,并使用混合效应模型通过报告几率比(ROR)进行量化。我们还评估了 ROR 水平与 AE 为无症状 ARIA 的先验概率之间的关联。我们对 28 项试验中的 6313 名注意力缺失症或轻度认知障碍患者进行了分析。在预设的 35 种神经精神或相关 AE 中,有几种 AE 的 ROR 显著较高:"妄想"(ROR = 4.133)、"混淆状态"(ROR = 1.419)、"肌肉痉挛"(ROR = 9.849)、"易激惹"(ROR = 12.62)、"睡眠障碍"(ROR = 2.944)或 "抽搐"(ROR = 13.00)。然而,在对迷你精神状态检查评分进行调整后,这些因素都不具有显著性。没有强有力的证据表明,在 APOE-ε4 携带者中,特定神经精神类 AEs 的发生率更高,且与药物治疗无关。在抗淀粉样蛋白β单克隆抗体治疗的安全性监测过程中,APOE-ε4等位基因对临床医生评估ARIA发生可能性的影响可能不会改变,从而保持临床医生对AEs的现有认识水平。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
APOE-ε4 allele[s]-associated adverse events reported from placebo arm in clinical trials for Alzheimer's disease: implications for anti-amyloid beta therapy
APOE-ε4 allele[s] is a risk factor for Alzheimer's disease (AD) and Amyloid-Related Imaging Abnormalities (ARIA) in anti-amyloid beta therapy, and is also associated with cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. During AD clinical trials, APOE-ε4 carriers may experience neuropsychiatric adverse events (AEs) related to these risks, complicating the differentiation of ARIA from cerebrovascular events based on symptoms. This study aimed to examine the hypothetical impact of considering the APOE-ε4 allele's risk for non-ARIA AEs during AD clinical trials. We used data from the Critical Path for Alzheimer's Disease (CPAD) from the placebo arm of randomized controlled trials (RCT) for AD treatment. We determined whether AEs were reported more frequently in APOE-ε4 carriers, quantifying with reporting odds ratio (ROR) using a mixed effect model. We also evaluated the association between ROR levels and the prior probability that an AE is symptomatic ARIA. We analyzed 6,313 patients with AD or mild cognitive impairment in 28 trials. Of the prespecified 35 neuropsychiatric or related AEs, several had a significantly high ROR: “delusion” (ROR = 4.133), “confusional state” (ROR = 1.419), “muscle spasms” (ROR = 9.849), “irritability” (ROR = 12.62), “sleep disorder” (ROR = 2.944), or “convulsion” (ROR = 13.00). However, none remained significant after adjusting for Mini-Mental State Examination scores. There is no strong evidence to suggest that specific neuropsychiatric AEs occur more frequently without drug treatment association among APOE-ε4 carriers. The influence of APOE-ε4 allele[s] on the clinicians' assessment of the likelihood of ARIA during safety monitoring in anti-amyloid beta monoclonal antibody treatment might be unchanged, thus maintaining the current level of awareness of clinicians of AEs.
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