将临床前阿尔茨海默病轨迹用于临床试验设计。

Use of preclinical Alzheimer's disease trajectories for clinical trial design.

作者信息

Langhough Rebecca E, Norton Derek L, Cody Karly A, Du Lianlian, Jonaitis Erin M, Wilson Rachael, Rea Reyes Ramiro Eduardo, Hermann Bruce P, Zetterberg Henrik, Johnson Sterling C

机构信息

Wisconsin Alzheimer's Institute, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53726, USA.

Wisconsin Alzheimer's Disease Research Center, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, 53792, USA.

出版信息

medRxiv. 2025 May 2:2025.05.01.25326668. doi: 10.1101/2025.05.01.25326668.

DOI:10.1101/2025.05.01.25326668

PMID:40657310

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12248167/

Abstract

INTRODUCTION

This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials.

METHODS

PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power).

RESULTS

To detect ≥60% slowing in PiB accumulation, ≤40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ~50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm.

DISCUSSION

Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.

摘要

引言

本研究使用纵向淀粉样蛋白生物标志物和认知数据，对双臂临床前淀粉样蛋白清除临床试验进行样本量估计。

方法

PET PiB DVR范围在认知未受损的威斯康星州阿尔茨海默病预防登记参与者中定义了三个淀粉样蛋白组（阳性，“A+”；亚阈值/低阳性，“subA+”；阴性，“A-”）。从混合效应模型估计的淀粉样蛋白组轨迹为每个治疗组的样本量估计提供了依据，以检测在3年（生物标志物）或6年（认知）研究窗口内可能的治疗效果（80%的检验效能）。