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Abstract：
BACKGROUND: Preclinical Alzheimer\'s disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer\'s disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities.
OBJECTIVE: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
METHODS: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
METHODS: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study.
METHODS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
METHODS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).
CONCLUSIONS: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer\'s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer\'s disease.
OBJECTIVE: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial.
METHODS: Phase 3, 4.5-year, multicenter, placebo-controlled trial.
METHODS: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer\'s Disease (A4) study.
METHODS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography.
METHODS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging).
RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001).
CONCLUSIONS: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer\'s disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer\'s disease.
摘要：
背景：临床前阿尔茨海默病在临床试验中的研究越来越多。尽管在阿尔茨海默病的临床试验人群中常规监测安全信号，根据与年龄相关的医疗合并症的背景发生率来识别新的安全性信号可能具有挑战性.
目的：报告来自认知未受损的老年人群的详细安全性数据，并在3期临床试验的安慰剂组的淀粉样蛋白正电子发射断层扫描中，有证据表明大脑淀粉样蛋白水平升高。
方法：第3阶段，4.5年，多中心，安慰剂对照试验。
方法：安慰剂数据来自无症状阿尔茨海默病（A4）的抗淀粉样蛋白治疗研究。
方法：注册的参与者年龄在65-85岁之间，总体临床痴呆评分为0，简易精神状态检查评分为25-30，韦氏记忆量表逻辑记忆IIa（延迟回忆）评分为6-18，在18F-florbetapir正电子发射断层扫描中，脑淀粉样蛋白水平升高。
方法：对接受安慰剂的研究参与者进行基线后安全措施的随访。评估包括合并用药和不良事件的回顾，哥伦比亚自杀严重程度等级量表,心电图,和神经成像（脑磁共振成像）。
结果：总计，591名研究参与者（平均年龄[标准差]71.9[5.0]岁）在A4研究中被分配并接受安慰剂，并随访了240周。参与者主要是白人（93.9%）和美国（86.8%）；60.4%是女性。最常见的严重不良事件（每100人年的发生率）是肺炎（发生率=0.4；95％置信区间=0.2-0.7）和心房颤动（发生率=0.4；95％置信区间=0.2-0.7）。最常见的治疗引起的不良事件是上呼吸道感染（发生率=10.9;95％置信区间=9.4-12.5）。跌倒(发生率=7.7；95%置信区间=6.6-9.0)，和鼻咽炎（发病率=5.8;95％置信区间=4.8-6.9）。磁共振成像中最常见的缺血相关发现是皮质下梗死（发生率=1.4；95％置信区间=1.0-2.0）和急性缺血（发生率=0.6；95％置信区间=0.3-1.0）。32.8%的安慰剂组患者出现淀粉样蛋白相关的影像学异常和含铁血黄素沉积;基线后阶段与这些事件相关的主要因素是基线时的微出血次数(比值比=349.9;95%置信区间=247.6-494.4;调整后p<0.001)。
结论：来自A4研究的安慰剂治疗组的安全性发现为临床前阿尔茨海默病的临床试验人群提供了预期安全性的有力表征。这些结果可能为正在进行的临床前阿尔茨海默病盲法研究中的未来研究和安全性评估提供背景。
目的：报告来自认知未受损的老年人群的详细安全性数据，并在3期临床试验的安慰剂组的淀粉样蛋白正电子发射断层扫描中，有证据表明大脑淀粉样蛋白水平升高。
方法：第3阶段，4.5年，多中心，安慰剂对照试验。
方法：安慰剂数据来自无症状阿尔茨海默病（A4）的抗淀粉样蛋白治疗研究。
方法：注册的参与者年龄在65-85岁之间，总体临床痴呆评分为0，简易精神状态检查评分为25-30，韦氏记忆量表逻辑记忆IIa（延迟回忆）评分为6-18，在18F-florbetapir正电子发射断层扫描中，脑淀粉样蛋白水平升高。
方法：对接受安慰剂的研究参与者进行基线后安全措施的随访。评估包括合并用药和不良事件的回顾，哥伦比亚自杀严重程度等级量表,心电图,和神经成像（脑磁共振成像）。
结果：总计，591名研究参与者（平均年龄[标准差]71.9[5.0]岁）在A4研究中被分配并接受安慰剂，并随访了240周。参与者主要是白人（93.9%）和美国（86.8%）；60.4%是女性。最常见的严重不良事件（每100人年的发生率）是肺炎（发生率=0.4；95％置信区间=0.2-0.7）和心房颤动（发生率=0.4；95％置信区间=0.2-0.7）。最常见的治疗引起的不良事件是上呼吸道感染（发生率=10.9;95％置信区间=9.4-12.5）。跌倒(发生率=7.7；95%置信区间=6.6-9.0)，和鼻咽炎（发病率=5.8;95％置信区间=4.8-6.9）。磁共振成像中最常见的缺血相关发现是皮质下梗死（发生率=1.4；95％置信区间=1.0-2.0）和急性缺血（发生率=0.6；95％置信区间=0.3-1.0）。32.8%的安慰剂组患者出现淀粉样蛋白相关的影像学异常和含铁血黄素沉积;基线后阶段与这些事件相关的主要因素是基线时的微出血次数(比值比=349.9;95%置信区间=247.6-494.4;调整后p<0.001)。
结论：来自A4研究的安慰剂治疗组的安全性发现为临床前阿尔茨海默病的临床试验人群提供了预期安全性的有力表征。这些结果可能为正在进行的临床前阿尔茨海默病盲法研究中的未来研究和安全性评估提供背景。
