Hou Xianhua, Huang Jiacheng, Wang Li, He Yuxuan, Song Jiaxing, Guo Changwei, Yang Shihai, Shi Xiaolei, Chen Lin, Liu Qu, Su Junfeng, Zeng Lin, Jiang Maojun, Chen Boyu, Cheng Xiangping, Chen Shengli, Pan Honghua, Shen Xiaoping, Wu Youlin, Tang Xionglin, Wang Jian, Han Shibo, Pu Tianqiang, Wu Changchuan, Li Fengguang, Qu Lunxue, Fu Zhong, Liu Hua, Li Yu, Mei Bin, Cheng Yanbo, Hu Zicheng, Zhang Haochun, Lv Tao, Wu Min, Xu Ruchuang, Ye Qinglin, Kong Liangbo, Mi Shuai, Wu Junhua, Wang Yu, Tian Zhenxuan, Sun Wenzhe, Ma Jinfu, Xu Xu, Wu Yazhou, Wang Duolao, Nogueira Raul G, Nguyen Thanh N, Saver Jeffrey L, Zi Wenjie, Zhou Zhenhua
Department of Neurology, The First Affiliated Hospital (Southwest Hospital), Army Medical University, Chongqing, China.
Department of Neurology, The Second Affiliated Hospital (Xinqiao Hospital), Army Medical University, Chongqing, China.
JAMA Neurol. 2025 Jul 5. doi: 10.1001/jamaneurol.2025.2036.
The optimal dose, safety, and efficacy of intra-arterial tenecteplase after successful reperfusion by endovascular thrombectomy for large vessel occlusion (LVO) is unknown.
To evaluate the dose-dependent adverse events and signals of efficacy of intra-arterial tenecteplase in LVO after successful reperfusion with thrombectomy, defined as an Extended Treatment in Cerebral Infarction score of 2b-3.
DESIGN, SETTING, AND PARTICIPANTS: This open-label, blinded-outcome assessment trial, incorporating a 14 + 8 dose-escalation (phase 1b, nonrandomized) and dose-expansion (phase 2a, randomized) design, was conducted in China between 2023 and 2024, with follow-up continuing through November 2024. This was a multicenter clinical trial including patients with LVO and successful reperfusion within 24 hours of last known well.
In phase 1b, intra-arterial tenecteplase, 0.0313, 0.0625, 0.1250, 0.1875 mg/kg; in phase 2a, intra-arterial tenecteplase 0.0313 or 0.0625 mg/kg, or control (without intra-arterial thrombolysis).
The primary outcome in phase 1b was symptomatic intracranial hemorrhage (sICH) within 24 hours. The primary outcome in phase 2a was 90-day no-disability outcome (modified Rankin Scale score 0-1).
A total of 205 patients (phase 1b: 48, phase 2a: 157) were enrolled and analyzed. The median (IQR) age was 71 (60-77) years, and 113 (55.1%) were male. In phase 1b, 1 of 14 and 2 of 22 patients with sICH were observed at dose tiers 0.0313 and 0.0625 mg/kg, respectively. Three of 12 patients had sICH at dose tier 0.1250 mg/kg, exceeding the prespecified safety threshold (P = .04). In phase 2a, eligible patients were randomly assigned to receive tenecteplase, 0.0313 mg/kg (n = 46) and 0.0625 mg/kg (n = 46), and 65 patients composed the control group. The primary outcome occurred in 22 of 65 patients (33.8%) in the control group, 17 of 46 patients (37.0%) in the tenecteplase, 0.0313 mg/kg, group (adjusted risk ratio [RR] vs control, 0.85; 95% CI, 0.54-1.35; P = .50), and 20 of 46 patients (43.5%) in the tenecteplase, 0.0625 mg/kg, group (adjusted RR, 1.15; 95% CI, 0.73-1.80; P = .55). No significant difference in the safety outcomes was observed among the 3 groups.
Results of this phase 1 and 2 randomized clinical trial reveal that adjunctive intra-arterial tenecteplase dosages of 0.0313 mg/kg or 0.0625 mg/kg after successful reperfusion in patients with anterior circulation LVO showed adequate safety to advance to larger trials to determine the potential therapeutic benefits.
ChiCTR.org.cn Identifier: ChiCTR2300073787 and ChiCTR2400080624.
对于大血管闭塞（LVO）患者，在血管内血栓切除术成功再灌注后，动脉内使用替奈普酶的最佳剂量、安全性和疗效尚不清楚。
评估动脉内使用替奈普酶在血栓切除术成功再灌注后的LVO患者中的剂量依赖性不良事件和疗效信号，再灌注成功定义为脑梗死扩展治疗评分2b - 3分。
设计、设置和参与者：这项开放标签、盲法结局评估试验采用了14 + 8剂量递增（1b期，非随机）和剂量扩展（2a期，随机）设计，于2023年至2024年在中国进行，随访持续至2024年11月。这是一项多中心临床试验，纳入了最后一次已知状态良好后24小时内发生LVO且再灌注成功的患者。
在1b期，动脉内使用替奈普酶，剂量分别为0.0313、0.0625、0.1250、0.1875 mg/kg；在2a期，动脉内使用替奈普酶剂量为0.0313或0.0625 mg/kg，或对照组（不进行动脉内溶栓）。
1b期的主要结局是24小时内出现症状性颅内出血（sICH）。2a期的主要结局是90天无残疾结局（改良Rankin量表评分0 - 1分）。
共纳入205例患者（1b期：48例，2a期：157例）并进行分析。中位（IQR）年龄为71（60 - 77）岁，113例（55.1%）为男性。在1b期，在0.0313和0.0625 mg/kg剂量组中，分别有1例和2例sICH患者；在0.1250 mg/kg剂量组中，12例患者中有3例出现sICH，超过了预先设定的安全阈值（P = 0.04）。在2a期，符合条件的患者被随机分配接受替奈普酶，0.0313 mg/kg（n = 46）和0.0625 mg/kg（n = 46），65例患者组成对照组。对照组65例患者中有22例（33.8%）发生主要结局，替奈普酶0.0313 mg/kg组46例患者中有17例（37.0%）（与对照组相比调整风险比[RR]为0.85；95%CI，0.54 - 1.35；P = 0.50），替奈普酶0.0625 mg/kg组46例患者中有20例（43.5%）（调整RR为1.15；95%CI，0.73 - 1.
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