常染色体显性阿尔茨海默病临床试验中基于生物标志物的疗效指标的样本量估计
Sample size estimates for biomarker-based outcome measures in clinical trials in autosomal dominant Alzheimer's disease.
作者信息
Cash David M, Morgan Katy E, O'Connor Antoinette, Veale Thomas D, Malone Ian B, Poole Teresa, Benzinger Tammie Ls, Gordon Brian A, Ibanez Laura, Li Yan, Llibre-Guerra Jorge J, McDade Eric, Wang Guoqiao, Chhatwal Jasmeer P, Day Gregory S, Huey Edward, Jucker Mathias, Levin Johannes, Niimi Yoshiki, Noble James M, Roh Jee Hoon, Sánchez-Valle Racquel, Schofield Peter R, Bateman Randall J, Frost Chris, Fox Nick C
机构信息
Dementia Research Centre, UCL Queen Square Institute of Neurology, First floor, 8-11 Queen Square, London, WC1N 3AR, UK.
UK Dementia Research Institute, 6th Floor, Maple House, Tottenham Court Road, London W1T 7NF, UK.
出版信息
medRxiv. 2025 Mar 7:2024.11.12.24316919. doi: 10.1101/2024.11.12.24316919.
INTRODUCTION
Alzheimer disease (AD)-modifying therapies are approved for treatment of early-symptomatic AD. Autosomal dominant AD (ADAD) provides a unique opportunity to test therapies in presymptomatic individuals.
METHODS
Using data from the Dominantly Inherited Alzheimer Network (DIAN), sample sizes for clinical trials were estimated for various cognitive, imaging, and CSF outcomes. Sample sizes were computed for detecting a reduction of either absolute levels of AD-related pathology (amyloid, tau) or change over time in neurodegeneration (atrophy, hypometabolism, cognitive change).
RESULTS
Biomarkers measuring amyloid and tau pathology had required sample sizes below 200 participants per arm (examples CSF Aβ42/40: 47[95%CI 25,104], cortical PIB 49[28,99], CSF p-tau181 74[48,125]) for a four-year trial in presymptomatic individuals (CDR=0) to have 80% power (5% statistical significance) to detect a 25% reduction in absolute levels of pathology, allowing 40% dropout. For cognitive, MRI, and FDG, it was more appropriate to detect a 50% reduction in rate of change. Sample sizes ranged from 250-900 (examples hippocampal volume: 338[131,2096], cognitive composite: 326[157,1074]). MRI, FDG and cognitive outcomes had lower sample sizes when including indivduals with mild impairment (CDR=0.5 and 1) as well as presymptomatic individuals (CDR=0).
DISCUSSION
Despite the rarity of ADAD, presymptomatic clinical trials with feasible sample sizes given the number of cases appear possible.
引言
用于改善阿尔茨海默病（AD）症状的疗法已被批准用于治疗早期有症状的AD。常染色体显性AD（ADAD）为在症状出现前的个体中测试治疗方法提供了独特的机会。
方法
利用来自显性遗传阿尔茨海默病网络（DIAN）的数据，对各种认知、成像和脑脊液结果的临床试验样本量进行了估计。计算样本量是为了检测AD相关病理（淀粉样蛋白、tau蛋白）的绝对水平降低或神经退行性变（萎缩、代谢减退、认知变化）随时间的变化。
结果
在症状出现前的个体（临床痴呆评定量表[CDR]=0）中进行为期四年的试验，要达到80%的检验效能（5%的统计学显著性）以检测病理绝对水平降低25%，同时允许40%的脱落率，测量淀粉样蛋白和tau蛋白病理的生物标志物每个组所需的样本量低于200名参与者（例如脑脊液Aβ42/40：47[95%置信区间25,104]，皮质匹兹堡化合物B[PIB]49[28,99]，脑脊液磷酸化tau181 74[48,125]）。对于认知、磁共振成像（MRI）和氟代脱氧葡萄糖（FDG），检测变化率降低50%更为合适。样本量范围为250 - 900（例如海马体积：338[131,2096]，认知综合评分：326[157,1074]）。当纳入轻度损害（CDR = 0.5和1）的个体以及症状出现前的个体（CDR = 0）时，MRI、FDG和认知结果的样本量较低。
讨论
尽管ADAD罕见，但鉴于病例数量，进行具有可行样本量的症状出现前临床试验似乎是可能的。
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