Intra-Arterial Tenecteplase After Successful Reperfusion in Large Vessel Occlusion Stroke: A Randomized Clinical Trial.
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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
Аннотация
OBJECTIVE: 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.
INTERVENTIONS: 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).
MAIN OUTCOMES AND MEASURES: 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).
RESULTS: 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.
CONCLUSIONS AND RELEVANCE: 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.
TRIAL REGISTRATION: ChiCTR.org.cn Identifier: ChiCTR2300073787 and ChiCTR2400080624.