Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Dementia Research Centre, Department of Neurodegenerative Disease, National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, 8-11 Queen Square, Box 16, London, WC1N 3BG, UK.
Alzheimers Res Ther. 2022 Jan 19;14(1):10. doi: 10.1186/s13195-022-00958-0.
Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design.
A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR® plus NACC-FTLD ≥ 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR® plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR® plus NACC-FTLD ≥ 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR® plus NACC-FTLD = 0.5 to ≥ 1 (and therefore how long a trial would need to be).
The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR® plus NACC-FTLD 0.5 to ≥ 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR® plus NACC FTLD 0.5 to ≥ 1 without treatment over that time period.
We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.
即将进行的额颞叶痴呆（FTD）治疗试验的临床终点越来越紧迫。认知综合评分通常用作终点，但在遗传性 FTD 中缺乏。我们旨在为遗传性额颞叶痴呆（FTD）创建认知综合评分，并为临床试验设计中的招募和持续时间提供建议。
对 69 名 C9orf72、41 名 GRN 和 28 名 MAPT 突变携带者进行了标准化神经心理学测试组合，这些携带者的 CDR®加上 NACC-FTLD ≥ 0.5，275 名对照。使用逻辑回归来确定区分每个突变携带者组和对照组的最佳测试组合。根据回归系数，从模型中的测试分数的加权平均值计算综合评分。对旨在预防从前驱期（CDR®加 NACC-FTLD 0.5）到完全症状期（CDR®加 NACC-FTLD ≥ 1）进展的理论试验中的单个认知测试和综合评分进行了样本量估计。进行时间事件分析以确定突变携带者从 CDR®加 NACC-FTLD = 0.5到≥1 的进展速度（因此试验需要多长时间）。
逻辑回归分析的结果导致每个突变携带者组（即 C9orf72、GRN 和 MAPT）的不同综合评分。与大多数个体测试相比，检测治疗效果的估计样本量较小。Kaplan-Meier 曲线显示，3 年后，约 50%的人从 CDR®加 NACC-FTLD 0.5转变为≥1，这意味着在样本量计算中需要将估计的效果大小减半，因为在这段时间内，只有一半的突变携带者预计会在没有治疗的情况下从 CDR®加 NACC FTLD 0.5进展到≥1。
我们为 C9orf72、GRN 和 MAPT 突变携带者创建了基因特异性认知综合评分，这导致检测治疗效果的估计样本量大大低于个体认知测试。GENFI-Cog 综合评分具有作为即将进行的临床试验认知终点的潜力。本研究结果为估计样本量和试验持续时间提供了建议。
Zotero 插件