Background/Aims:

The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power.

Methods:

We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes.

Results:

Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau.

Conclusion:

Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

中文翻译：

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关于脑脊液 tau 结局的早期阿尔茨海默病临床试验的设计

 背景/目标：

阿尔茨海默病研究的重点已转向疾病的早期阶段，包括轻度认知障碍。生物标志物纳入标准通常被纳入轻度认知障碍临床试验中，以识别患有“前驱阿尔茨海默病”的个体，以确保适当的药物靶点并丰富可能发展为阿尔茨海默病痴呆的参与者。这些资格标准的使用可能会影响研究能力。

 方法：

我们调查了概念验证前驱阿尔茨海默病试验中的结果变异性和研究功效，其中将脑脊液中总 tau (t-tau) 和磷酸化 (p-tau) 水平作为主要结果，以及不同生物标志物纳入标准的影响力量。我们使用阿尔茨海默病神经影像计划的数据来模拟试验场景，并估计总 tau 蛋白和磷酸化 tau 蛋白的方差和受试者内相关性。然后，这些估计被用来调查考虑这两种替代结果的试验的研究效力的差异。

 结果：

所有资格标准的患者特征均相似。与β淀粉样蛋白或总tau蛋白相比，无论使用总tau蛋白还是磷酸化tau蛋白作为主要结果，当使用磷酸化tau蛋白作为资格标准时，获得了最低的结果方差和最高的受试者内相关性。当扩大资格标准以允许招募具有低淀粉样蛋白 β 或高磷酸化 tau 的受试者时，权力就会增加。

 结论：

特定的生物标志物纳入标准可能会影响使用总 tau 或磷酸化 tau 作为主要结果的试验的统计功效。与治疗目标和临床感兴趣人群等其他重要考虑因素相一致，这些结果可能对前驱阿尔茨海默病试验设计的完整性和效率产生影响。