Safety and efficacy of crenezumab in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at risk for autosomal-dominant Alzheimer's disease in Colombia (API ADAD Colombia Trial): a phase 2, randomised, double-blind, placebo-controlled trial.

Mutations of the PSEN1 gene are inherited as fully penetrant, autosomal-dominant traits, which almost always result in the clinical onset of Alzheimer's disease before the age of 65 years.

PSEN1基因的突变以完全显性的自体遗传方式遗传，几乎总是导致65岁之前出现阿尔茨海默病的临床发病。

We aimed to evaluate the efficacy, including possible delayed emergence of cognitive impairment, and safety of crenezumab, an anti-amyloid monoclonal antibody, in cognitively unimpaired carriers of the PSEN1Glu280Ala mutation at high imminent risk of developing symptoms due to Alzheimer's disease.

我们旨在评估抗淀粉样蛋白单克隆抗体crenezumab在认知未受损的PSEN1Glu280Ala突变携带者中的疗效，这些携带者因阿尔茨海默病而面临高风险即将出现症状，包括可能的认知损害延迟出现，以及其安全性。

Methods

This 5-8-year common-close, double-blind, placebo-controlled, single-centre trial screened kindred members aged 30-60 years from the main health-care site in Medellín, Colombia.

这项为期5-8年的共同密切、双盲、安慰剂对照、单中心试验，在哥伦比亚麦德林的主要医疗中心筛选了30-60岁的家族成员。

Participants who were cognitively unimpaired and carried the PSEN1Glu280Ala autosomal-dominant mutation were randomly assigned 1:1 to receive placebo or subcutaneous crenezumab (investigators and participants were masked to treatment allocation), with an initial 300 mg dose every 2 weeks that increased to 720 mg every 2 weeks, and a later optional increase to 60 mg/kg intravenously every 4 weeks.

认知未受损且携带PSEN1Glu280Ala常染色体显性突变的参与者被随机分配为1:1接受安慰剂或皮下注射crenezumab（研究者和参与者对治疗分配不知情），初始剂量为每两周300 mg，增加至每两周720 mg，随后可选择增加至每四周静脉注射60 mg/kg。

Randomisation was stratified by age, education, APOE ɛ4 carrier status, and baseline Clinical Dementia Rating.

随机分配按年龄、教育程度、APOE ɛ4携带状态和基线临床痴呆评分进行分层。

Mutation non-carriers received placebo and were included in a 1:2 ratio of non-carriers to carriers to maintain genotype masking and include a genetic kindred control.

未携带突变的受试者接受了安慰剂，并按照1:2的比例包括非携带者和携带者，以保持基因型的掩蔽并包括一个遗传亲属对照。

Dual primary outcomes were the annualised rates of change in the Alzheimer's Prevention Initiative (API) preclinical autosomal-dominant Alzheimer's disease (ADAD) composite test total score and Free and Cued Selective Reminding Test-Cueing Index (FCSRT-CI) assessed in randomised participants who received at least one dose of the study drug, according to treatment assignment.

双重主要结果是根据治疗分配，在接受至少一剂研究药物的随机参与者中，评估阿尔茨海默病预防倡议（API）前临床常染色体显性阿尔茨海默病（ADAD）综合测试总分和自由及提示性选择性提醒测试-提示指数（FCSRT-CI）的年化变化率。

Primary endpoints were assessed with a random coefficient regression model with a missing-at-random assumption adjusting for randomisation factors.

主要终点通过随机系数回归模型进行评估，该模型假设数据缺失是随机的，并对随机化因素进行了调整。

Safety endpoints for mutation carriers were assessed in randomised participants who received at least one dose of the study drug.

在至少接受一次研究药物剂量的随机参与者中，评估了突变携带者的安全性终点。

This trial is registered with ClinicalTrials.gov (NCT01998841) and is completed.

该试验已在ClinicalTrials.gov注册（NCT01998841），并已完成。

Results

619 Colombian API registrants were prescreened, 315 were assessed for eligibility, and 252 were enrolled (crenezumab-carrier, n=85; placebo-carrier, n=84; placebo-non-carrier, n=83; 160 [63%] women and 92 [37%] men) between Dec 20, 2013, and Feb 27, 2017. 237 (94%) completed the trial, with final data collection on March 22, 2022.

在2013年12月20日至2017年2月27日期间，对619名哥伦比亚API注册者进行了预筛选，其中315人被评估是否符合资格，最终有252人被纳入试验（crenezumab携带者，n=85；安慰剂携带者，n=84；安慰剂非携带者，n=83；160名[63%]女性和92名[37%]男性）。有237人（94%）完成了试验，最后一次数据收集于2022年3月22日完成。

The annualised rate of change in the API ADAD composite was -1·10 (SE 0·29) in the crenezumab group and -1·43 (0·29) in the placebo group (between-group difference 0·33 [95% CI -0·48 to 1·13]; p=0·43).

API ADAD综合评分的年化变化率在克伦珠单抗组为-1.10（标准误0.29），在安慰剂组为-1.43（标准误0.29）（组间差异0.33 [95% 置信区间-0.48至1.13]；p=0.43）。

The annualised rate of change in FCSRT-CI was -0·03 (0·00) in the crenezumab group and -0·04 (0·00) in the placebo group (between-group difference 0·01 [0·00 to 0·02]; p=0·16).

FCSRT-CI的年化变化率在克伦珠单抗组为-0.03（标准误0.00），在安慰剂组为-0.04（标准误0.00）（组间差异0.01 [0.00至0.02]；p=0.16）。

All participants had at least one adverse event; serious adverse events occurred in 23 (27%) of 84 in the crenezumab group and 21 (25%) of 84 in the placebo group.

所有参与者至少经历了一次不良事件；在84名接受克瑞那珠单抗治疗的患者中，有23例（27%）发生了严重不良事件，在84名接受安慰剂治疗的患者中，有21例（25%）发生了严重不良事件。

No fatalities occurred.

没有发生任何死亡事件。

interpretation

Crenezumab therapy administered for 5-8 years did not result in significant benefits on our primary clinical outcomes in cognitively unimpaired participants predisposed to developing ADAD dementia; secondary and exploratory outcomes also showed no significant effect on removal of amyloid plaques or other clinical or biomarker outcomes.

Crenezumab治疗5-8年并未在认知未受损但有发展为ADAD痴呆倾向的参与者中显著改善我们的主要临床结果；次要和探索性结果也显示对清除淀粉样斑块或其他临床或生物标志物结果没有显著影响。

Together with the results of other anti-amyloid β trials, robust fibrillar amyloid removal appears necessary for clinical efficacy in people with elevated brain amyloid.

与其他抗淀粉样β试验的结果相结合，对于脑内淀粉样蛋白水平升高的人群，显著的纤维状淀粉样蛋白清除似乎对于临床疗效是必要的。

This study will further inform the biomarker, cognitive, and clinical trajectory of preclinical ADAD, the risk of clinical progression in amyloid-positive and amyloid-negative mutation carriers, and the size and design of future secondary and primary prevention trials.

本研究将进一步阐明前临床ADAD的生物标志物、认知和临床轨迹，淀粉样蛋白阳性与阴性突变携带者的临床进展风险，以及未来二级和一级预防试验的规模和设计。

funding

US National Institute on Aging (NIA), Banner Alzheimer's Institute, Genentech, F Hoffmann-La Roche.

美国国家老龄化研究所（NIA）、Banner阿尔茨海默病研究所、基因科技公司、F Hoffmann-La Roche。