Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer's disease.
Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer's disease.
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DOI：
10.1186/s13195-023-01183-z
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发表时间：
2023-03-06
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目前迫切需要设计新的主要终点，以检测针对阿尔茨海默病（AD）无症状（临床前）阶段的临床试验中认知的早期和微妙变化。阿尔茨海默氏症预防计划（API）生成计划，在有患AD风险的认知未受损个体中进行（例如，通过载脂蛋白E（APOE）基因型富集），使用了一种新的双重主要终点方法，其中证明两个终点之一的治疗效果足以使试验成功。两个主要终点是（1）至事件发生时间（TTE）-事件定义为AD所致轻度认知功能障碍（MCI）和/或AD所致痴呆的诊断-和（2）API临床前综合认知（APCC）测试评分从基线至第60个月的变化。来自三个来源的历史观察数据被用来拟合模型来描述TTE和纵向APCC下降，无论是在谁做和不进展到MCI或痴呆症由于AD的人。基于TTE和APCC模型模拟临床终点，以评估双终点相对于两个单终点的性能，选定的治疗效应范围为风险比（HR）0.60（风险降低40%）至1（无效应）。TTE选择Weibull模型，分别选择功效和线性模型描述进展者和非进展者的APCC评分。从基线至第5年APCC变化降低方面的推导效应量较低（HR = 0.67时为0.186）。单独APCC的把握度始终低于单独TTE的把握度（HR = 0.67时，58% [APCC] vs 84% [TTE]）。此外，TTE和APCC之间的家族1型错误率（α）分布为80%/20%（82%）的总体把握度高于20%/80%（74%）。在有AD风险的认知未受损人群（基于APOE基因型）中，双终点（包括TTE和认知下降指标）的表现优于认知下降指标作为单一主要终点。然而，在这一人群中进行的临床试验需要规模较大，包括年龄较大的患者，并且需要至少5年的长期随访才能检测治疗效果。在线版本包含补充材料，可通过10.1186/s13195-023-01183-z获得。
There is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer’s disease (AD). The Alzheimer’s Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)—with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD—and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score. Historical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect). A Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%). Dual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects. The online version contains supplementary material available at 10.1186/s13195-023-01183-z.
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影响因子：
29
作者：
Donohue, Michael C.;Sperling, Reisa A.;Salmon, David P.;Rentz, Dorene M.;Raman, Rema;Thomas, Ronald G.;Weiner, Michael;Aisen, Paul S.
通讯作者：
Aisen, Paul S.
影响因子：
5.3
作者：
Bonham, Luke W.;Geier, Ethan G.;Fan, Chun C.;Leong, Josiah K.;Besser, Lilah;Kukull, Walter A.;Kornak, John;Andreassen, Ole A.;Schellenberg, Gerard D.;Rosen, Howard J.;Dillon, William P.;Hess, Christopher P.;Miller, Bruce L.;Dale, Anders M.;Desikan, Rahul S.;Yokoyama, Jennifer S.
通讯作者：
Yokoyama, Jennifer S.
在阿尔茨海默氏病临床试验中测量神经认知功能的新方法。
影响因子：
4.8
作者：
Carlson, Scott;Kim, Hyun;Devanand, Davangere P.;Goldberg, Terry E.
通讯作者：
Goldberg, Terry E.
影响因子：
2.2
作者：
Reiman EM;Langbaum JB;Tariot PN
通讯作者：
Tariot PN
DOI：
10.1002/alz.12773
发表时间：
2023-03
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Jutten RJ;Papp KV;Hendrix S;Ellison N;Langbaum JB;Donohue MC;Hassenstab J;Maruff P;Rentz DM;Harrison J;Cummings J;Scheltens P;Sikkes SAM
通讯作者：
Sikkes SAM