Neuronavigation-assisted Stereotactic Minimally Invasive Puncture With Tenecteplase for Acute Lobar Intracerebral Hemorrhage

Phase 3Not Yet RecruitingNCT07471256

Beijing Tiantan Hospital636 enrolled

Overview

Introduction: Minimally invasive puncture surgery with thrombolysis is effective for hypertensive intracerebral hemorrhage, but its effect on neurological recovery remains uncertain. The use of neuronavigation-assisted stereotactic technology can significantly improve the precision of catheter placement, while tenecteplase (TNK), a third-generation thrombolytic with high fibrin specificity and superior activity against platelet-rich clots. Nonetheless, the efficacy and safety of combining neuronavigation-assisted stereotactic minimally invasive puncture (NALCIE) with TNK for reducing disability and mortality in acute spontaneous lobar intracerebral hemorrhage have yet to be established. Aim: To present the scientific rationale and study design of the neuronavigation-assisted stereotactic minimally invasive puncture combined with tenecteplase (NALICE-TNK) trial for the treatment of acute spontaneous lobar intracerebral hemorrhage. Design: NALICE-TNK is a multicenter, randomized, open-label, assessor-blinded, clinical trial enrolling 636 patients with acute lobar intracerebral hemorrhage and hematoma volumes of 30-50 mL. The trial aims to assess the efficacy and safety of neuronavigation-assisted stereotactic minimally invasive puncture (MIPS) combined with tenecteplase (TNK), administered every 24 hours at a dose of 0.009 mg per mL of hematoma volume, versus standard medical care. All participants will undergo standardized 180-day follow-up. Study outcomes: The primary efficacy endpoint is functional ambulation (a score of 0 to 3 on the modified Rankin scale; range, 0 to 6, with higher scores indicating more severe disability) at 180 days. The primary safety endpoint is all-cause mortality at 30 days.

The 2024 Brief Report on Stroke Prevention and Treatment in China indicates that the incidence rate of spontaneous intracerebral hemorrhage in China was 61/100,000 in 2021. Among these, acute spontaneous lobar intracerebral hemorrhage has become a major cause of stroke and related deaths, resulting in high disability and mortality rate. The surgical treatment of lobar hemorrhage has been a prominent research focus in neurosurgery. The STICH Ⅱ trial demonstrated that, for patients with spontaneous supratentorial lobar hemorrhage, early craniotomy for hematoma evacuation did not significantly improve functional prognosis compared to conservative medical treatment. Nevertheless, the ENRICH trial showed that, compared to standard medical treatment, early stereotactic minimally invasive puncture and drainage significantly improved the 90-day functional prognosis of patients with acute intracerebral hemorrhage, with this benefit also being robust in the lobar hemorrhage subgroup. The study further underscores that minimally invasive surgery is not universally applicable: patient selection requires systematic integration of multiple evidence-informed factors, including hematoma volume and morphology, deep versus lobar anatomical location, time from symptom onset to intervention, baseline neurological severity (e.g., NIHSS score), and major systemic comorbidities, into a comprehensive, individualized treatment decision. In the 2022 guidelines for intracerebral hemorrhage, minimally invasive procedures (MIPS) are recommended as a Class 2a intervention due to their mortality-reducing benefit. MIPS under stereotactic or neuronavigation guidance represents a technically sound approach with relatively robust evidence and high clinical accessibility. It is highly standardized and has low dependence on medical resources, making it feasible for implementation in centers with basic neuroimaging and perioperative management capabilities. Several multicenter randomized controlled trials, such as MISTIE II, MISTIE III, and ENRICH, have confirmed that minimally invasive techniques, including stereotactic minimally invasive puncture and drainage and neuroendoscopic hematoma evacuation, can significantly reduce the 90-day all-cause mortality rate in patients with spontaneous intracerebral hemorrhag. In these studies, the mortality rate in the minimally invasive treatment group was lower than that in the corresponding standard medical treatment control group. Despite baseline differences, pooled data show 90-day mortality was 18-26% with standard medical treatment and 9-19% with minimally invasive treatment. Although MIPS has been proven to reduce surgical complications compared to craniotomy, its efficacy in reducing long-term neurological dysfunction remains uncertai. In the STICH trial, the incidence of neurological dysfunction in the minimally invasive puncture group was 36.1%, higher than 26.5% in the conservative treatment group. Similarly, the MISTIE II trial, led by the Hanley team, observed a similar trend, with the 90-day composite endpoint of disability or death in the minimally invasive puncture group being 73.0%, slightly higher than 69.0% in the conservative treatment group. However, in the more rigorous MISTIE III trial, this endpoint difference between the two groups was no longer statistically significant (71.8% vs. 72.0%, P = 0.94). It is noteworthy that the subgroup analysis of the MISTIE III trial showed that patients who received minimally invasive surgery and had their postoperative residual hematoma volume reduced to \<15 mL experienced significantly better 90-day functional outcome compared to those in the standard medical treatment group. This suggests that extensive and rapid hematoma evacuation can effectively improve patient prognosis. Therefore, future trials should prospectively assess whether combining early aggressive evacuation with minimally invasive surgery can outperform the current standard and further enhance functional outcomes. Precise localization of the catheter tip at the center of the hematoma is essential for efficient hematoma evacuation, as it directly influences the gravity-dependent diffusion distribution of thrombolytic agents within the hematoma cavity, thereby determining the efficiency of clot dissolution. The liquefied hematoma components are also drained through the same catheter. The combination of neuronavigation and stereotactic techniques significantly improves the accuracy of target localization. Additionally, preoperative planning based on CT angiography helps avoid blood vessels, reducing the risk of brain tissue injury and secondary hemorrhage due to puncture. Tenecteplase (TNK), a third-generation tissue plasminogen activator derived from alteplase (rt-PA), offers several significant pharmacological advantages. Firstly, TNK has a substantially longer plasma half-life than rt-PA, allowing for a single intravenous bolus administration instead of the continuous infusion required by rt-PA, simplifying the clinical medication regimen and enhancing operational feasibility. Secondly, TNK has greater resistance to plasminogen activator inhibitor-1 (PAI-1), helping maintain stable enzymatic activity and thereby enhancing thrombolytic efficacy, especially in treating hematoma formation secondary to acute intracerebral hemorrhage, with potential benefits. Furthermore, TNK has higher specificity for fibrin, selectively activating plasminogen within local thrombi while reducing systemic plasminogen activation, thereby effectively minimizing bleeding complications, including severe or diffuse bleeding events. These pharmacological properties have been validated in numerous large-scale clinical studies on myocardial infarction and acute ischemic stroke. Recent studies have also shown that TNK can accelerate the enzymatic degradation and clearance of blood clots, thus facilitating hematoma resolution. However, high-quality evidence supporting the effectiveness and safety of neuronavigation-assisted stereotactic minimally invasive puncture combined with TNK (NALICE-TNK) in improving functional prognosis in patients with acute spontaneous lobar hemorrhage is currently lacking. The NALICE-TNK trial aims to determine whether neuronavigation-guided stereotactic minimally invasive puncture combined with tenecteplase improves functional outcomes in patients with acute spontaneous lobar intracerebral hemorrhage compared to standard drug therapy. This multicenter, randomized, outcome-blinded trial will evaluate the efficacy and safety of neuronavigation-assisted stereotactic minimally invasive puncture combined with thrombolysis using tenecteplase in reducing disability and mortality rates in patients with spontaneous lobar intracerebral hemorrhage. This article outlines the design and protocol of the trial.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥18 years and \<80 years 2. Symptoms must have manifested within 24 hours prior to the diagnostic CT (dCT) scan. Patients with indeterminate symptom onset are excluded; for those who awoke with symptoms, the last known well time is used. 3. Acute spontaneous lobar intracerebral hemorrhage (ICH) occurring in the frontal lobe, parietal lobe, temporal lobe, or occipital lobe, with a volume between 30-50 mL, measured at the site using the ABC/2 method with radiographic imaging (CT, etc.). 4. Glasgow Coma Scale (GCS) score of 5-14. 5. Stability CT scan done at least 6 hours after diagnostic CT showing clot stability (growth\<5 mL as measured by ABC/2 method). 6. Randomization should occur within 6 to 24 hours after the diagnostic CT. 7. Systolic blood pressure (SBP) less than 180 mmHg maintained for a duration of six hours, documented proximate to the randomization time point. 8. Historical modified Rankin (mRS) score of 0 or 1. Exclusion Criteria: 1. Hemorrhage in the basal ganglia, thalamus, or subtentorial region, including posterior fossa and cerebellar hemorrhage. 2. Stability CT scan done at least 6 hours after diagnostic CT showing clot instability (growth ≥5 mL as measured by ABC/2 method). 3. Intraventricular hemorrhage necessitating intervention to address mass effect or midline shift attributable to trapped ventricle syndrome secondary to intraventricular hemorrhage (IVH)-related casting. 4. Hemorrhage attributable to other cerebrovascular pathologies, including but not limited to ruptured aneurysm, arteriovenous malformation (AVM), vascular anomalies, moyamoya disease, hemorrhagic transformation of an ischemic infarct, or recurrence of a recent hemorrhage within the past year, as diagnosed through radiographic imaging. 5. Patients presenting with an unstable intracranial mass or progressive intracranial compartment syndrome. 6. National Institutes of Health Stroke Scale (NIHSS) score ≤ 5. 7. Presence of puncture contraindications. 8. Irreversible impairment of brainstem function, characterized by bilateral fixed and dilated pupils, extensor motor posturing, and a Glasgow Coma Scale (GCS) score of ≤ 4. 9. Indications for craniotomy in patients include: 1) progressive impairment of consciousness; 2) presence of brain herniation, with signs related to cerebellar tonsil herniation or temporal lobe gyrus herniatio. 10. CT evidence suggesting a high risk of rebleeding, such as spot sign. 11. Platelet count \<100,000/mL; INR \>1.4. 12. Any irreversible coagulation disorders (e.g., hemophilia, von Willebrand disease, use of anticoagulants such as warfarin) or known clotting disorders (e.g., hypercoagulable states). 13. Inability to maintain INR ≤1.4 using short-acting and long-acting procoagulants (e.g., recombinant human coagulation factor VIIa, fresh frozen plasma, vitamin K, etc.). 14. Subjects necessitating long-term anticoagulation therapy are excluded from participation. Reversal of anticoagulation is permissible for medically stable patients who can feasibly tolerate the short-term risks associated with reversal. Patients must not require coumadin (warfarin) or other anticoagulants during the initial 8-week period. 15. Prior to the onset of symptoms, anticoagulants such as dabigatran, apixaban, or rivaroxaban, as well as treatments like tirofiban, ticagrelor, cilostazol, or clopidogrel, were used. 16. Internal bleeding involving the retroperitoneal, gastrointestinal, or genitourinary system, or respiratory tract bleeding. 17. Superficial or surface bleeding, observed mainly at vascular puncture and access sites (e.g., venous cutdowns, arterial punctures, etc.) or site of recent surgical intervention. 18. Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization. 19. Allergy/sensitivity to TNK. 20. Prior enrollment in the study. 21. Engagement in a concurrent interventional clinical investigation or trial. Patients enrolled in observational, natural history, or epidemiological studies that do not involve any form of intervention remain eligible. 22. Not expected to survive until the day 180 visit due to co-morbidities, or having DNR/DNI status (Do-Not-Resuscitate and Do-Not-Intubate) prior to randomization. 23. The presence of any concurrent serious illness that could confound outcome assessments, including but not limited to hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders. 24. Patients with mechanical heart valves are excluded. The presence of bioprosthetic valve (s) is permissible. 25. Known risk for embolization, including history of left heart thrombus, mitral stenosis with atrial fibrillation, acute pericarditis, or subacute bacterial endocarditis. Atrial fibrillation without mitral stenosis is permitted. 26. Any other condition that, in the investigator's judgment, would present a significant risk to the subject if the investigational therapy were to be initiated. 27. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. 28. Patients deemed by the investigator to have unstable conditions that may benefit from other treatments. 29. Patients requesting conservative treatment or standard craniotomy microsurgery treatment. 30. The subject or their legal guardian/representative demonstrates an inability or lack of willingness to provide written informed consent.

Outcomes

Primary Outcomes

Proportion of participants with mRS 0-3 at 180 days

The primary outcome is the proportion of participants with a modified Rankin Scale (mRS) score of 0-3 (range, 0 to 6, with higher scores indicating more severe disability) at 180 days.

Time frame: 180 ±14 days

All-cause death at 30 days post-randomization

Time frame: 30-day post-randomization period

Secondary Outcomes

Functional independence of patients with adjudicated mRS of 0-2 at 180 days post-randomization.

Functional independence of patients with adjudicated mRS of 0-2 at 180 days post-randomization. The mRS is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-2=No symptoms to slight disability; 3-6=Moderate disability requiring some assistance to death.

Time frame: 180 ± 14 days

Excellent functional outcome of patients with adjudicated mRS of 0-1 at 180 days post-randomization.

Excellent functional outcome of patients with adjudicated mRS of 0-1 at 180 days post-randomization. The mRS is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death.

Time frame: 180 ±14 days

Distribution of mRS scores (0-6) at 180 days post-randomization.

Distribution of mRS scores (0-6) at 180 days post-randomization. The mRS is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death.

Time frame: 180 ± 14 days

Distribution of mRS scores (0-6) at 30 days post-randomization

Distribution of mRS scores (0-6) at 30 days post-randomization. The mRS is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death.

Time frame: 30 days post-randomization

Residual hematoma volume at 24 hours post the final administration.

The residual volume of the hematoma was calculated through CT examination 24 hours after the last administration of TNK (using the ABC/2 method).

Time frame: 24 hours after the last administration of TNK

Dichotomized eGOS (extended Glasgow Outcome Scale) score at 180 days: 4-8 (good) vs. 1-3(poor)

Dichotomized eGOS (extended Glasgow Outcome Scale) score at 180 days: 4-8 (good) vs. 1-3 (poor). The eGOS is scored as: 1=Death, 2=Vegetative state, 3=Lower severe disability, 4=Upper severe disability, 5=Lower moderate disability, 6=Upper moderate disability, 7=Lower good recovery, 8=Upper good recovery.

Time frame: 180 ± 14 days

Functional ambulation of patients with mRS scores of 0-3 (good functional outcome) at 90 days post-randomization.

Functional ambulation of patients with mRS scores of 0-3 (good functional outcome) at 90 days post-randomization. The mRS is scored from: 0=No symptoms at all, 1=No significant disability, 2=Slight disability, 3=Moderate disability, 4=Moderately severe disability, 5=Severe disability and 6=death. Dichotomized scores are: 0-3=No symptoms to moderate disability requiring some assistance; 4-6=Moderately severe disability requiring complete assistance to death.

Time frame: 90 ± 7 days

All-cause death at 180 days post-randomizationl

All-cause death at 180 days post-randomizationl.

Time frame: 180 ± 14 days

Barthel Index (BI) assessment at 180 days post-randomization

Barthel Index (BI) assessment at 180 days post-randomization. The Barthel Index (BI) assesses ten functional tasks of daily living, and each task provides a measure for level of independence. Scores range from 0 and 100, with a higher score indicating greater independence.

Time frame: 180 ±14 days

Extended Glasgow Outcome (eGOS) assessment at 180 days post-randomization

Extended Glasgow Outcome (eGOS) assessment at 180 days post-randomization. The extended Glasgow Outcome Scale (eGOS) is a global scale for functional outcome with eight categories: 1 - Death, 2 - Vegetative State, 3 - Lower Severe Disability, 4 - Upper Severe Disability, 5 - Lower Moderate Disability, 6 - Upper Moderate Disability, 7 - Lower Good Recovery, 8 - Upper Good Recovery.

Time frame: 180 ± 14 days

The change of the National Institutes of Health Stroke Scale (NIHSS) at 5-7 days or discharge if earlier from baseline

The change of the National Institutes of Health Stroke Scale (NIHSS) at 5-7 days or discharge if earlier from baseline. Patients with a NIHSS score of less than 6 are considered to have a good recovery. The NIHSS is a 11-item scale that assesses language, motor function, sensory loss, consciousness, visual fields, extraocular movements, coordination, neglect, and speech. It is scored from 0 (no stroke symptoms) to 42 (severe stroke).

Time frame: 5-7 days

Symptomatic rebleeding events within 7 days post-randomization

Symptomatic rebleeding events within 7 days post-randomization (defined as a persistent decrease in GCS motor score by more than 2 points, with a CT scan showing a new hematoma with a CT value greater than 72 HU and a volume exceeding 5 ml within the hematoma cavity and surrounding area compared to the prior scan).

Time frame: Within 7 days

All-cause death at 7 days

Time frame: Within 7 days

30-day intracranial bacterial infection post-randomization

Intracranial bacterial infection within 30 days.

Time frame: Within 30 days

Total Adverse Events (AEs) within 30 and 180 days

Total Adverse Events (AEs) across all coded organ systems that occurred within 30 and 180 days.

Time frame: Within 30 and 180 days

Total Serious Adverse Events (SAEs) within 30 and 180 days

Time frame: Within 30 and 180 days

Neuronavigation-assisted Stereotactic Minimally Invasive Puncture With Tenecteplase for Acute Lobar Intracerebral Hemorrhage

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts