Phase I dose-escalation study of tenecteplase, a third-generation fibrinolytic agent, combined with neuronavigation-assisted stereotactic minimally invasive puncture, in patients with acute spontaneous deep cerebral haemorrhage.

Introduction: Tenecteplase (TNK) offers logistical advantages in stroke thrombolytic therapy with its single bolus administration compared with alteplase. Moreover, its high specificity for fibrin may contribute to a reduction in haemorrhage complications. However, the safety, tolerability and efficacy of TNK, combined with neuronavigation-assisted stereotactic minimally invasive puncture, in patients with acute spontaneous deep cerebral haemorrhage remain unknown.

Methods: We conducted a prospective, open-label phase I trial in a 3+3 dose escalation design to evaluate the safety and tolerability, and maximum tolerated dose (MTD) of TNK in patients with acute spontaneous basal ganglia or thalamic haemorrhage, with haematoma volumes ranging from 20 to 50 mL, combined with neuronavigation-assisted stereotactic minimally invasive puncture surgery (MIPS). During the dose-escalation phases of the trial, patients received intra-haematoma injection of TNK via a haematoma evacuation catheter every 24 hours after surgery until three doses were administered or any termination criteria were met (residual haematoma ≤10 mL or rebleeding event), with doses ranging from 0.001 to 0.003 and 0.009 mg per mL of haematoma volume. The primary safety endpoint was drug-related rebleeding during the dose escalation phases, while the primary efficacy endpoint was the mean drug-related haematoma clearance per dose.

Results: In total, 12 patients were recruited. No drug-related rebleeding events at any dose escalation phase occurred. By the 24 hours after the last dose, the residual haematoma volume for each patient across all groups was reduced to less than 10 mL. The 0.009 mg TNK dose group achieved the highest mean haematoma clearance of 17.49 mL per dosing. The MTD was 0.009 mg/mL of haematoma volume in the dose escalation phase.

Discussion and conclusion: TNK is well tolerated with encouraging signs of dissolving blood clots. Further exploration of TNK combined with neuronavigation-assisted stereotactic MIPS in patients with acute spontaneous deep cerebral haemorrhage is warranted.

Trial registration number: NCT06668441.