Importance: The optimal dose, safety, and efficacy of intra-arterial tenecteplase after successful reperfusion by endovascular thrombectomy for large vessel occlusion (LVO) is unknown.
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.