Robot-Assisted Hematoma Evacuation With Intrahematoma Tenecteplase for Post-Reperfusion PH2 Hemorrhagic Transformation

A Phase I, Open-Label, Single-Arm Study of Robot-Assisted Stereotactic Minimally Invasive Hematoma Aspiration Followed by Intrahematoma Tenecteplase in Patients With Symptomatic Supratentorial PH2 Hemorrhagic Transformation After Reperfusion Therapy for Acute Ischemic Stroke

The purpose of this phase I trial is to evaluate the safety and feasibility of robot-assisted stereotactic minimally invasive hematoma aspiration, followed when eligible by intrahematoma tenecteplase administration, in patients who develop symptomatic supratentorial PH2 hemorrhagic transformation after reperfusion therapy for acute ischemic stroke. The main study questions are whether this strategy is associated with an acceptable early rebleeding risk and whether it can achieve clinically meaningful hematoma reduction with accurate catheter placement and relief of hematoma-related mass effect.

Symptomatic intracranial hemorrhage after reperfusion therapy is one of the most devastating complications of acute ischemic stroke and is associated with high mortality, especially in patients with PH2 hemorrhagic transformation and substantial mass effect. Current management is largely supportive and includes discontinuation of antithrombotic agents, correction of coagulation abnormalities, blood pressure control, and intracranial pressure management. However, medical treatment does not remove the hematoma or reverse the local toxic and space-occupying effects of blood products.

Open craniotomy may be lifesaving in selected patients, but it may also cause additional injury to already ischemic and vulnerable brain tissue. Robot-assisted stereotactic minimally invasive puncture and aspiration may provide a less disruptive method to evacuate hematoma, reduce mass effect, and preserve surrounding tissue. A prior phase I neuronavigation-assisted minimally invasive puncture study in spontaneous deep intracerebral hemorrhage identified 0.009 mg/mL of hematoma-volume-adjusted tenecteplase as the highest tested dose with acceptable safety and the greatest mean hematoma clearance. Because the present trial targets a different and higher-risk population, namely post-reperfusion therapy PH2 hemorrhagic transformation, the study remains phase I in intent but uses a fixed dose rather than a dose-escalation design.

This is a prospective, open-label, single-arm phase I trial enrolling 20 participants with symptomatic supratentorial PH2 hemorrhagic transformation after reperfusion therapy (intravenous thrombolysis, with or without bridging mechanical thrombectomy). Eligible hematomas may be deep or lobar and must be associated with clinically relevant neurological worsening and hematoma-related mass effect. Before puncture, all participants must undergo protocol-based correction of coagulation abnormalities and at least one stability CT scan confirming no ongoing rapid expansion. Robot-assisted stereotactic aspiration and catheter placement will then be performed. A repeat CT approximately 2 hours later must confirm no procedure-related rebleeding before intrahematoma tenecteplase is started.

Tenecteplase will be administered once daily through the indwelling catheter at a fixed dose of 0.009 mg/mL of residual hematoma volume, for up to 3 doses. Each dose will be diluted to 1 mL with sterile water for injection, followed by a 3 ml normal saline flush. The catheter will remain clamped for 2 hours and then reopened for drainage. Treatment will stop when any termination criterion is met, including symptomatic rebleeding, radiographic hematoma enlargement, residual hematoma of 10 mL or less, or completion of 3 doses.

The primary objective is safety, particularly symptomatic rebleeding within 72 hours after the procedure or first tenecteplase dose, defined as clinically relevant hematoma expansion at the original cavity or catheter tract accompanied by neurological deterioration. The main efficacy and feasibility objectives are to determine whether the procedure achieves protocol-defined hematoma reduction-residual hematoma volume<15 mL or <33% of baseline volume by end-of-treatment CT-and accurate catheter placement within 3 mm of the planned target on immediate postoperative imaging. Secondary outcomes include residual hematoma volume at Day 7 or end of treatment, the proportion of participants achieving residual hematoma ≤10 mL, any radiographic rebleeding through Day 7, and procedure-related serious adverse events（SAE） through Day 7.

Inclusion Criteria:

•. Age 18 years or older and younger than 80 years.

• Prestroke modified Rankin Scale score of 0 to 2.
• Acute ischemic stroke treated with reperfusion therapy (standard-dose intravenous thrombolysis using alteplase or tenecteplase, or mechanical thrombectomy or any other endovascular reperfusion procedure for the index stroke).
• CT-confirmed symptomatic PH2 hemorrhagic transformation according to ECASS criteria in a supratentorial deep or lobar location, with hematoma-related mass effect and/or midline shift.
• Hematoma volume 20 to 80 mL measured by ABC/2 method.
• Neurological deterioration attributed to hemorrhagic transformation, defined as an NIHSS increase of 4 points or more from the best post-thrombolysis status or a GCS decrease of 2 points or more.
• At least one repeat stability CT scan obtained 6 hours or more after the diagnostic CT showing no ongoing rapid expansion, defined as hematoma growth less than 6 mL.
• Planned robot-assisted stereotactic minimally invasive puncture/aspiration within 24 hours after the diagnostic CT.
• Completion of intravenous thrombolytic infusion at least 4 hours before final preprocedure assessment, with protocol-based reversal/correction of coagulopathy as needed.
• Preprocedure coagulation thresholds achieved after reversal/correction: INR < 1.4 or less, and fibrinogen > 1.6 g/L.
• Systolic blood pressure 180 mmHg or less maintained for at least 6 hours before the procedure.
• Written informed consent provided by the participant or legally authorized representative.

Exclusion Criteria:

• HI1, HI2, or PH1 hemorrhagic transformation without clinically relevant mass effect.
• Infratentorial hemorrhage, including brainstem or cerebellar hemorrhage.
• Large malignant hemispheric infarction in which the dominant cause of mass effect is ischemic edema rather than hematoma, or clear need for decompressive craniectomy as first-line treatment.
• Hemorrhage primarily attributable to aneurysm, arteriovenous malformation, dural arteriovenous fistula, moyamoya disease, tumor, trauma, or another structural lesion; or hemorrhage caused predominantly by a procedural vascular injury unrelated to thrombolysis-associated hemorrhagic transformation.
• Intraventricular hemorrhage requiring separate emergency surgical treatment as the dominant lesion.
• Irreversible brainstem failure, bilateral fixed and dilated pupils, or GCS score of 4 or less.
• Ongoing hematoma expansion on stability CT, defined as growth of 6 mL or more.
• Imaging evidence of active bleeding or markedly high rebleeding risk, such as spot sign, if judged unsafe for catheter aspiration.
• Need for long-term anticoagulation that cannot be safely interrupted during the first 30 days after treatment.
• No safe robot-planned stereotactic trajectory to the hematoma cavity.
• Severe hepatic, renal, cardiac, respiratory, or hematologic illness likely to confound assessment or markedly increase procedural risk.
• Pregnancy or breastfeeding.
• Known allergy or hypersensitivity to alteplase or tenecteplase.
• Participation in another interventional clinical trial.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for this study.