Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease

医学 安慰剂 不利影响 随机对照试验 内科学 临床痴呆评级 痴呆 认知功能衰退 生物标志物 临床试验 神经心理学 认知 评定量表 疾病 心理学 精神科 病理 发展心理学 化学 替代医学 生物化学
作者
Reisa A. Sperling,David Henley,Paul S. Aisen,Rema Raman,Michael Donohue,Karin Ernström,Michael S. Rafii,Johannes Streffer,Yingqi Shi,Keith Karcher,Nandini Raghavan,Yevgen Tymofyeyev,Jennifer Bogert,H. Robert Brashear,Gerald Novak,John Thipphawong,Ziad S. Saad,Hartmuth C. Kolb,Hany Rofael,Panna Sanga,Gary Romano
出处
期刊:JAMA Neurology [American Medical Association]
卷期号:78 (3): 293-293 被引量:66
标识
DOI:10.1001/jamaneurol.2020.4857
摘要

Atabecestat, a nonselective oral β-secretase inhibitor, was evaluated in the EARLY trial for slowing cognitive decline in participants with preclinical Alzheimer disease. Preliminary analyses suggested dose-related cognitive worsening and neuropsychiatric adverse events (AEs).To report efficacy, safety, and biomarker findings in the EARLY trial, both on and off atabecestat treatment, with focus on potential recovery of effects on cognition and behavior.Randomized, double-blind, placebo-controlled, phase 2b/3 study conducted from November 2015 to December 2018 after being stopped prematurely. The study was conducted at 143 centers across 14 countries. Participants were permitted to be followed off-treatment by the original protocol, collecting safety and efficacy data. From 4464 screened participants, 557 amyloid-positive, cognitively normal (Clinical Dementia Rating of 0; aged 60-85 years) participants (approximately 34% of originally planned 1650) were randomized before the trial sponsor stopped enrollment.Participants were randomized (1:1:1) to atabecestat, 5 mg (n = 189), 25 mg (n = 183), or placebo (n = 185).Primary outcome: change from baseline in Preclinical Alzheimer Cognitive Composite score. Secondary outcomes: change from baseline in the Cognitive Function Index and the Repeatable Battery for the Assessment of Neuropsychological Status total scale score. Safety was monitored throughout the study.Of 557 participants, 341 were women (61.2%); mean (SD) age was 70.4 (5.56) years. In May 2018, study medication was stopped early owing to hepatic-related AEs; participants were followed up off-treatment for 6 months. Atabecestat, 25 mg, showed significant cognitive worsening vs placebo for Preclinical Alzheimer Cognitive Composite at month 6 (least-square mean difference, -1.09; 95% CI, -1.66 to -0.53; P < .001) and month 12 (least-square mean, -1.62; 95% CI, -2.49 to -0.76; P < .001), and at month 3 for Repeatable Battery for the Assessment of Neuropsychological Status (least-square mean, -3.70; 95% CI, -5.76 to -1.63; P < .001). Cognitive Function Index participant report showed nonsignificant worsening at month 12. Systemic and neuropsychiatric-related treatment-emergent AEs were greater in atabecestat groups vs placebo. After stopping treatment, follow-up cognitive testing and AE assessment provided evidence of reversibility of drug-induced cognitive worsening and AEs in atabecestat groups.Atabecestat treatment was associated with dose-related cognitive worsening as early as 3 months and presence of neuropsychiatric treatment-emergent AEs, with evidence of reversibility after 6 months off treatment.ClinicalTrials.gov Identifier: NCT02569398.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
ajin发布了新的文献求助30
1秒前
Ben完成签到,获得积分10
3秒前
1111完成签到,获得积分10
3秒前
liu完成签到,获得积分10
4秒前
5秒前
SciGPT应助超级的抽屉采纳,获得10
5秒前
汉堡包应助慎独采纳,获得10
7秒前
研友_nqa7On发布了新的文献求助10
7秒前
廖紊驳回了李健应助
7秒前
xutong de完成签到,获得积分10
8秒前
ticsadis完成签到,获得积分10
8秒前
辛勤梦桃发布了新的文献求助10
9秒前
Anthea完成签到,获得积分10
9秒前
10秒前
10秒前
10秒前
爆米花应助栗子采纳,获得10
11秒前
慕青应助vivian26采纳,获得10
12秒前
陆柯川完成签到,获得积分10
12秒前
Planetary完成签到 ,获得积分10
13秒前
Juan发布了新的文献求助10
13秒前
13秒前
14秒前
科研通AI2S应助anan采纳,获得10
14秒前
奈落完成签到 ,获得积分10
15秒前
兴奋笑天发布了新的文献求助10
16秒前
陆柯川发布了新的文献求助10
16秒前
猫尾巴发布了新的文献求助30
18秒前
威武鹤轩完成签到 ,获得积分10
18秒前
上官若男应助llk采纳,获得10
20秒前
Juan完成签到,获得积分20
20秒前
21秒前
李健应助张三采纳,获得10
22秒前
科目三应助zoeylau采纳,获得30
23秒前
23秒前
超速也文章完成签到,获得积分20
24秒前
张萝卜完成签到,获得积分10
25秒前
科研奇才发布了新的文献求助10
25秒前
猫尾巴完成签到,获得积分10
26秒前
高分求助中
Evolution 10000
ISSN 2159-8274 EISSN 2159-8290 1000
Becoming: An Introduction to Jung's Concept of Individuation 600
A new species of Coccus (Homoptera: Coccoidea) from Malawi 500
A new species of Velataspis (Hemiptera Coccoidea Diaspididae) from tea in Assam 500
PraxisRatgeber: Mantiden: Faszinierende Lauerjäger 500
The Kinetic Nitration and Basicity of 1,2,4-Triazol-5-ones 440
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3159888
求助须知:如何正确求助?哪些是违规求助? 2810893
关于积分的说明 7889801
捐赠科研通 2469910
什么是DOI,文献DOI怎么找? 1315243
科研通“疑难数据库(出版商)”最低求助积分说明 630761
版权声明 602012