晚期急性缺血性脑卒中应用抗炎溶栓 JX10（TMS-007）
Anti-Inflammatory Thrombolytic JX10 (TMS-007) in Late Presentation of Acute Ischemic Stroke.
机构信息
Department of Neurosurgery (K.N., T.T.),Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Neurosurgical Engineering and Translational Neuroscience (K.N.), Tohoku University Graduate School of Medicine, Sendai, Japan.
出版信息
Stroke. 2024 Dec;55(12):2786-2794. doi: 10.1161/STROKEAHA.124.048464. Epub 2024 Nov 7.
BACKGROUND
Contemporary thrombolytics in acute ischemic stroke are limited to administration within 4.5 hours of last known normal. JX10 (formerly TMS-007), a triprenyl phenol family member, may extend this therapeutic window.
METHODS
In this multicenter, randomized, double-blind, placebo-controlled, dose-escalation phase 2a study, JX10 or placebo was administered as a single intravenous infusion to Japanese patients with acute ischemic stroke who were unable to receive tissue-type plasminogen activator or thrombectomy within 12 hours of last known normal. Primary end point was incidence of symptomatic intracranial hemorrhage with a worsening National Institutes of Health Stroke Scale score of ≥4 points within 24 hours of drug administration (symptomatic intracranial hemorrhage incidence).
RESULTS
Ninety patients received either placebo (n=38; female 26.3%) or JX10 at 1, 3, or 6 mg/kg (n=6, 18, 28; female 0%, 33.3%, and 42.9%, respectively). Median age (range) and baseline median (range) National Institutes of Health Stroke Scale scores were respectively 76.5 (42-87) and 8 (6-21) for the combined JX10 cohort (JX10 Cohorts) and 75.0 (34-85) and 8 (6-22) for placebo. Median (range) dosing time since last known normal was 9.5 (5.0-12.1) and 10.0 (3.7-12.0) hours for JX10 Cohorts and placebo, respectively. Symptomatic intracranial hemorrhage incidence was 0% (0/52 [95% CI, 0.0-5.6]) for JX10 Cohorts versus 2.6% (1/38 [95% CI, 0.1-13.8]) for placebo (=0.42). Vessel patency at 24 hours (secondary end point) in patients with baseline arterial occlusive lesion score <3 (39/90) improved in 58.3% (14/24) of patients in JX10 Cohorts versus 26.7% (4/15) for placebo (odds ratio, 4.23 [95% CI, 0.99-18.07]). In JX10 Cohorts, a significantly higher proportion of patients had modified Rankin Scale scores of 0 to 1 on day 90 (secondary end point) versus placebo (JX10: 21/52, 40.4% versus placebo: 7/38, 18.4%; =0.03).
CONCLUSIONS
JX10 was well tolerated and may expand the acute ischemic stroke therapeutic window as a novel thrombolytic agent.
REGISTRATION
URL: https://rctportal.niph.go.jp/en; Unique identifier: jRCT2080223786.
背景
目前用于急性缺血性脑卒中的溶栓药物的治疗时间窗限制在最后一次可识别正常时间的 4.5 小时内。JX10（前称 TMS-007）是一种三萜酚家族成员，可能会延长这个治疗时间窗。
方法
在这项多中心、随机、双盲、安慰剂对照、剂量递增的 2a 期研究中，JX10 或安慰剂作为单次静脉输注，用于最后一次可识别正常时间 12 小时内无法接受组织型纤溶酶原激活物或血栓切除术的日本急性缺血性脑卒中患者。主要终点是给药后 24 小时内出现症状性颅内出血，且美国国立卫生研究院卒中量表评分恶化≥4 分（症状性颅内出血发生率）。
结果
90 例患者接受安慰剂（n=38；女性 26.3%）或 JX10 1、3 或 6mg/kg（n=6、18、28；女性 0%、33.3%和 42.9%）。联合 JX10 队列（JX10 队列）的中位年龄（范围）和基线中位数（范围）美国国立卫生研究院卒中量表评分分别为 76.5（42-87）和 8（6-21），而安慰剂组分别为 75.0（34-85）和 8（6-22）。自最后一次可识别正常时间的中位数（范围）给药时间分别为 JX10 队列和安慰剂的 9.5（5.0-12.1）和 10.0（3.7-12.0）小时。症状性颅内出血发生率为 JX10 队列 0%（0/52[95%置信区间，0.0-5.6%]），安慰剂组为 2.6%（1/38[95%置信区间，0.1-13.8%]）（=0.42）。基线动脉闭塞病变评分<3 的患者（90 例中的 39 例）在 24 小时时血管再通（次要终点）的比例，在 JX10 队列中为 58.3%（14/24），而安慰剂组为 26.7%（4/15）（比值比，4.23[95%置信区间，0.99-18.07]）。在 JX10 队列中，90 天时改良 Rankin 量表评分 0-1 的患者比例明显高于安慰剂组（JX10：21/52，40.4%比安慰剂：7/38，18.4%；=0.03）。
结论
JX10 具有良好的耐受性，可能作为一种新型溶栓药物扩大急性缺血性脑卒中的治疗时间窗。
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