Reactions to Multiple Ascending Doses of the Microtubule Stabilizer TPI-287 in Patients With Alzheimer Disease, Progressive Supranuclear Palsy, and Corticobasal Syndrome

进行性核上麻痹 耐受性 医学 临床试验 内科学 匹兹堡化合物B 安慰剂 皮质基底变性 阿尔茨海默病 疾病 病理 不利影响 替代医学
作者
Richard Tsai,Zachary Miller,Mary Koestler,Julio C. Rojas,Peter A. Ljubenkov,Howard J. Rosen,Gil D. Rabinovici,Anne M. Fagan,Yann Cobigo,Jesse A. Brown,Joo In Jung,Emma Hare,David Geldmacher,Marissa Natelson-Love,Emily C. McKinley,Phi N. Luong,Emmeline L. Chuu,Ryan Powers,Paige Mumford,Amy Wolf,Ping Wang,Mehrdad Shamloo,Bruce L. Miller,Erik D. Roberson,Adam L. Boxer
出处
期刊:JAMA Neurology [American Medical Association]
卷期号:77 (2): 215-215 被引量:94
标识
DOI:10.1001/jamaneurol.2019.3812
摘要

Importance

Basket-design clinical trials that allow investigation of treatment effects on different clinical syndromes that share the same molecular pathophysiology have not previously been attempted in neurodegenerative disease.

Objective

To assess the safety, tolerability, and pharmacodynamics of the microtubule stabilizer TPI-287 (abeotaxane) in Alzheimer disease (AD) or the 4-repeat tauopathies (4RT) progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

Design, Setting, and Participants

Two parallel-design, double-blind, placebo-controlled phase 1 randomized clinical trials in AD and 4RT were conducted from December 20, 2013, through May 4, 2017, at the University of California, San Francisco, and University of Alabama at Birmingham. A total of 94 patients with clinically diagnosed AD (n = 39) and 4RT (n = 55) were screened; of these, 3 refused to participate, and 10 with AD and 11 with 4RT did not meet inclusion criteria. A total of 29 patients with AD, 14 with PSP, and 30 with β-amyloid–negative CBS (determined on positron emission tomography findings) were enrolled. Data were analyzed from December 20, 2013, through May 4, 2017, based on modified intention to treat.

Interventions

Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension.

Main Outcomes and Measures

Primary end points were safety and tolerability (maximal tolerated dose) of TPI-287. Secondary and exploratory end points included TPI-287 levels in cerebrospinal fluid (CSF) and changes on biomarker, clinical, and neuropsychology measures.

Results

A total of 68 participants (38 men [56%]; median age, 65 [range, 50-85] years) were included in the modified intention-to-treat analysis, of whom 26 had AD (14 women [54%]; median age, 63 [range, 50-76] years), and 42 had 4RT (16 women [38%]; median age, 69 [range, 54-83] years). Three severe anaphylactoid reactions occurred in TPI-287–treated patients with AD, whereas none were seen in patients with 4RT, leading to a maximal tolerated dose of 6.3 mg/m2for AD and 20.0 mg/m2for 4RT. More falls (3 in the placebo group vs 11 in the TPI-287 group) and a dose-related worsening of dementia symptoms (mean [SD] in the CDR plus NACC FTLD-SB [Clinical Dementia Rating scale sum of boxes with frontotemporal dementia measures], 0.5 [1.8] in the placebo group vs 0.7 [1.6] in the TPI-287 group; median difference, 1.5 [95% CI, 0-2.5];P = .03) were seen in patients with 4RT. Despite undetectable TPI-287 levels in CSF, CSF biomarkers demonstrated decreased chitinase-3–like protein-1 (YKL-40) levels in the 4RT treatment arm (mean [SD], −8.4 [26.0] ng/mL) compared with placebo (mean [SD], 10.4 [42.3] ng/mL; median difference, −14.6 [95% CI, −30.0 to 0.2] ng/mL;P = .048, Mann-Whitney test).

Conclusions and Relevance

In this randomized clinical trial, TPI-287 was less tolerated in patients with AD than in those with 4RT owing to the presence of anaphylactoid reactions. The ability to reveal different tau therapeutic effects in various tauopathy syndromes suggests that basket trials are a valuable approach to tau therapeutic early clinical development.

Trial Registration

ClinicalTrials.gov identifiers:NCT019666666andNCT02133846
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
刚刚
义气高丽完成签到 ,获得积分10
刚刚
李博士发布了新的文献求助30
刚刚
小圆圈发布了新的文献求助10
刚刚
Hello应助皮皮采纳,获得10
3秒前
大面包发布了新的文献求助10
3秒前
华仔应助可爱的芷云采纳,获得10
5秒前
Orange应助Chrisiu采纳,获得10
5秒前
5秒前
萧寒发布了新的文献求助30
5秒前
fujun0095发布了新的文献求助10
6秒前
6秒前
啊啊啊发布了新的文献求助20
6秒前
wu发布了新的文献求助10
7秒前
8秒前
8秒前
令狐冲完成签到,获得积分10
9秒前
Ava应助dalin采纳,获得10
9秒前
10秒前
yyauthor完成签到,获得积分10
11秒前
好的发布了新的文献求助10
11秒前
12秒前
Owen应助小熊软糖采纳,获得10
12秒前
皮皮完成签到,获得积分10
12秒前
OK佛发布了新的文献求助10
13秒前
13秒前
团子发布了新的文献求助10
14秒前
粗心的荷花完成签到 ,获得积分10
16秒前
皮皮发布了新的文献求助10
16秒前
刘汉淼完成签到,获得积分10
16秒前
16秒前
封听白完成签到,获得积分10
17秒前
zhang发布了新的文献求助10
17秒前
18秒前
明亮的一瓶完成签到 ,获得积分10
18秒前
NexusExplorer应助绿色催化采纳,获得10
19秒前
tb168tb完成签到,获得积分10
19秒前
zgsjymysmyy发布了新的文献求助10
19秒前
21秒前
21秒前
高分求助中
The Oxford Handbook of Social Cognition (Second Edition, 2024) 1050
Kinetics of the Esterification Between 2-[(4-hydroxybutoxy)carbonyl] Benzoic Acid with 1,4-Butanediol: Tetrabutyl Orthotitanate as Catalyst 1000
The Young builders of New china : the visit of the delegation of the WFDY to the Chinese People's Republic 1000
юрские динозавры восточного забайкалья 800
English Wealden Fossils 700
Handbook of Qualitative Cross-Cultural Research Methods 600
Chen Hansheng: China’s Last Romantic Revolutionary 500
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 3140041
求助须知:如何正确求助?哪些是违规求助? 2790931
关于积分的说明 7797066
捐赠科研通 2447278
什么是DOI,文献DOI怎么找? 1301808
科研通“疑难数据库(出版商)”最低求助积分说明 626340
版权声明 601194