Memory and Aging Center, Department of Neurology, Sandler Neurosciences Center, University of California, San Francisco.
Department of Radiology and Biomedical Imaging, University of California, San Francisco.
JAMA Neurol. 2020 Feb 1;77(2):215-224. doi: 10.1001/jamaneurol.2019.3812.
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.
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.
Randomization was 8:3 drug to placebo in 3 sequential dose cohorts receiving 2.0, 6.3, or 20.0 mg/m2 of intravenous TPI-287 once every 3 weeks for 9 weeks, with an optional 6-week open-label extension.
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.
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/m2 for AD and 20.0 mg/m2 for 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).
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.
ClinicalTrials.gov identifiers: NCT019666666 and NCT02133846.
以前从未在神经退行性疾病中尝试过允许针对具有相同分子病理生理学的不同临床综合征进行治疗效果研究的篮子设计临床试验。
评估微管稳定剂 TPI-287（abeotaxane）在阿尔茨海默病（AD）或 4 重复 tau 病（4RT）进行性核上性麻痹（PSP）和皮质基底节综合征（CBS）中的安全性、耐受性和药效动力学。
设计、设置和参与者：这是一项在加利福尼亚大学旧金山分校和阿拉巴马大学伯明翰分校进行的 2 项平行设计、双盲、安慰剂对照的 1 期随机临床试验，于 2013 年 12 月 20 日至 2017 年 5 月 4 日进行。共有 94 名临床诊断为 AD（n=39）和 4RT（n=55）的患者接受了筛选；其中 3 人拒绝参与，10 名 AD 患者和 11 名 4RT 患者不符合纳入标准。共纳入 29 名 AD 患者、14 名 PSP 患者和 30 名β-淀粉样蛋白阴性 CBS（根据正电子发射断层扫描结果确定）患者。基于修改后的意向治疗进行了 2013 年 12 月 20 日至 2017 年 5 月 4 日的数据分析。
随机分为 3 个顺序剂量组，每组 8 名患者接受 2.0、6.3 或 20.0mg/m2 的静脉 TPI-287，每 3 周 1 次，共 9 周，可选 6 周的开放标签扩展。
主要终点是 TPI-287 的安全性和耐受性（最大耐受剂量）。次要和探索性终点包括 TPI-287 在脑脊液（CSF）中的水平以及生物标志物、临床和神经心理学测量的变化。
共有 68 名参与者（38 名男性[56%]；中位年龄 65[范围 50-85]岁）纳入修改后的意向治疗分析，其中 26 名患有 AD（14 名女性[54%]；中位年龄 63[范围 50-76]岁），42 名患有 4RT（16 名女性[38%]；中位年龄 69[范围 54-83]岁）。3 名 AD 患者在接受 TPI-287 治疗时发生严重类过敏反应，而 4RT 患者中未发生，导致 AD 的最大耐受剂量为 6.3mg/m2，4RT 为 20.0mg/m2。4RT 组更多的跌倒（安慰剂组 3 例，TPI-287 组 11 例）和与剂量相关的痴呆症状恶化（CDR 加 NACC FTLD-SB[临床痴呆评定量表总分与额颞叶痴呆措施]的平均[标准差]，安慰剂组 0.5[1.8]，TPI-287 组 0.7[1.6]；中位数差异，1.5[95%CI，0-2.5]；P=0.03）。尽管 CSF 中未检测到 TPI-287 水平，但 CSF 生物标志物显示 4RT 治疗组的几丁质酶-3 样蛋白-1（YKL-40）水平降低（平均[标准差]，-8.4[26.0]ng/mL）与安慰剂组（平均[标准差]，10.4[42.3]ng/mL；中位数差异，-14.6[95%CI，-30.0 至 0.2]ng/mL；P=0.048，曼-惠特尼检验）。
在这项随机临床试验中，由于类过敏反应的存在，TPI-287 在 AD 患者中的耐受性低于 4RT 患者。能够在各种 tau 病综合征中显示不同的 tau 治疗效果表明，篮子试验是 tau 治疗早期临床开发的一种有价值的方法。
ClinicalTrials.gov 标识符：NCT019666666 和 NCT02133846。
