Clinical trial NCT06868511: Neuronavigation-assisted Stereotactic Puncture With Tenecteplase for Acute Intracerebral Hemorrhage
Official title: Neuronavigation-assisted Stereotactic Minimally Invasive Puncture Combined With Tenecteplase for the Treatment of Acute Spontaneous Deep Intracerebral Hemorrhage(NAS-TNK)： a Randomized, Outcome-blinded, Multi-center Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Deep Intracerebral Hemorrhage (ICH)
Keywords: Tenecteplase
Neuronavigation-assisted Stereotactic
Deep intracerebral hemorrhage
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
First posted: 2025-03-11
Enrollment: 732
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background Minimally invasive puncture surgery followed by thrombolysis has been proven to be an effective approach for managing hypertensive intracerebral hemorrhage. Nevertheless, its impact on improving neurological outcomes remains controversial. The integration of neuronavigation-assisted stereotactic (NAS) technology will significantly help enhance the accuracy of catheter placement, while tenecteplase (TNK), a third-generation thrombolytic agent, with greater potency in lysing platelet-rich clots and heightened specificity for fibrin may improve thrombolysis efficiency. However, the efficacy and safety of combining NAS minimally invasive puncture combined with TNK in reducing disability and mortality rates among patients with acute spontaneous deep intracerebral hemorrhage remain unknown.

Aim To evaluate the efficacy and safety of neuronavigation-assisted stereotactic MIPS combined with TNK thrombolysis （NAS-TNK）in reducing disability and mortality in patients with deep hypertensive intracerebral hemorrhage.

Design NAS-TNK is a randomized, open-label, outcome-blinded multicenter trial, involving 732 participants with acute basal ganglia or thalamic hemorrhage with a hematoma volume ranging from 20-50 mL. This study will evaluate the efficacy and safety of NAS minimally invasive puncture combined with TNK, administered every 24 hours at a dose of 0.009 mg per milliliter of hematoma volume, compared to participants receiving standard medical care. All patients will be followed up for 180 days.

Study outcomes The primary efficacy outcome is the proportion of subjects in the NAS-TNK group with a modified Rankin Scale (mRS) score between 0 and 3 at 180 days. The primary safety outcome is the all-cause death at 30-day.

The NAS-TNK study will help improve our understanding of the benefits of NAS minimally invasive puncture combined with TNK in patients with acute spontaneous deep intracerebral hemorrhage. This ongoing research will provide Level I evidence to guide clinicians in managing acute intracerebral hemorrhage treatment options.

Detailed description: Every year, more than 5 million cases of brain hemorrhage are reported worldwide. Minimally invasive surgery (MIS) has been established as an effective approach for treating acute spontaneous intracerebral hemorrhage and has received endorsement from both international and national clinical guidelines. Randomized controlled trials, such as MISTIE II, MISTIE III, and ENRICH, have demonstrated that procedures involving minimally invasive puncture or endoscopic hematoma evacuation significantly lower mortality rates among patients suffering from intracerebral hemorrhage. Data from these studies indicate that the mortality rate in the minimally invasive treatment groups has decreased from 18% to 26% down to approximately 9% to 19%. Additionally, the 2022 guidelines published by the American Heart Association and the American Stroke Association recommend these minimally invasive techniques as the preferred surgical intervention for patients with hematoma volumes exceeding 20 to 30 milliliters.

Minimally invasive puncture surgery (MIPS) combined with thrombolysis is particularly favored for its simplicity and broad applicability. This technique effectively aids in the evacuation of hematomas and alleviates pressure in cases of deep acute spontaneous intracerebral hemorrhages, all while minimizing the risk of iatrogenic injury and maximizing the protection of neural tissue. Although MIPS has shown promising outcomes in reducing procedure-related trauma, the long-term effectiveness of this method in preventing neurological deficits remains a subject of ongoing debate. Recent findings from the MISTIE III trial shed light on this issue. In this trial, the MISTIE group exhibited a mortality rate of 15% at 180 days, a significant reduction compared to the 23% observed in the standard care group (p=0.033). Furthermore, at 365 days, 45% of patients treated with MIPS achieved a modified Rankin Scale (mRS) score of 0 to 3, indicating favorable functional outcomes, compared to 41% in the standard medical care group, with no statistically significant difference observed between the two groups.

Nonetheless, subgroup analyses from the MISTIE III trial indicated that patients who underwent surgical intervention and achieved a hematoma reduction to less than 15 mL experienced significantly improved functional outcomes compared to those who received conservative treatment. This suggests that, in clinically stable patients, more aggressive and rapid removal of intracerebral hematomas may effectively lower the risk of mortality and enhance functional outcomes. Therefore, conducting trials that focus on rapid and extensive removal of hematoma volumes combined with MIPS would be beneficial in achieving better functional results.

The precise placement of the catheter tip within the hematoma is critical for the efficient and rapid evacuation of intracerebral hematoma. The thrombolytic agent delivered from the catheter tip relies on gravity to infiltrate and interact with the clot, thereby facilitating its dissolution. Simultaneously, the liquefied hematoma fluid is drained through the catheter tip. Neuronavigation-assisted stereotactic (NAS) technology can significantly enhance the accuracy of catheter tip placement, thereby reducing the risk of iatrogenic injuries and complications.

Tenecteplase (TNK), a third-generation thrombolytic agent derived from alteplase (rt-PA), offers several advantages over its predecessor. Its extended half-life allows for rapid administration via bolus infusion, providing logistical benefits compared to rt-PA. Additionally, TNK demonstrates increased resistance to inactivation by plasminogen activator inhibitor-1, resulting in a greater potency for lysing platelet-rich clots. Its heightened specificity for fibrin may also contribute to a reduction in hemorrhagic complications, especially those associated with systemic bleeding. These benefits have been evidenced in studies focused on conditions such as myocardial infarction and acute ischemic stroke. TNK has also shown effective thrombolytic effects, aiding in the dissolution of clots and promoting hematoma clearance. However, the efficacy and safety of combining NAS-assisted minimally invasive puncture with TNK (NAS-TNK) to reduce disability and mortality rates in patients with acute spontaneous deep intracerebral hemorrhage remain uncertain.

The NAS-TNK trial is designed to explore the impact of precise, rapid, and efficient clearance of hematoma volumes on the improvement of neurological function in patients. This multicenter, randomized, outcome-blinded study will evaluate the efficacy and safety of neuronavigation-assisted stereotactic MIPS combined with TNK thrombolysis in reducing disability and mortality rates in patients suffering from deep hypertensive intracerebral hemorrhage. This paper presents the design of the NAS-TNK trial and outlines its protocol in detail.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years and \<80 years.
2. Symptoms must have manifested within 24 hours prior to the diagnostic CT (dCT) scan. Cases with an indeterminate onset time are excluded. For patients who present symptoms upon sleeping, the last known time they were well should be used.
3. Acute spontaneous deep intracerebral hemorrhage (ICH) occurring in the basal ganglia or thalamus, with a volume between 20-50 mL as measured by 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 Rankin score of 0 or 1.

Exclusion Criteria:

1. Lobar or subtentorial hemorrhage, including posterior fossa hemorrhage 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. Thalamic hemorrhages exhibiting evident extension into the midbrain, accompanied by oculomotor nerve palsy or pupils that are dilated and non-reactive. Other supranuclear gaze abnormalities do not constitute exclusion criteria.
7. Irreversible impairment of brainstem function, characterized by bilateral fixed and dilated pupils, extensor motor posturing, and a Glasgow Coma Scale (GCS) score of ≤ 4.
8. 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 herniation; 3) hematoma located within 1 cm of the cortical surface.
9. CT evidence suggesting a high risk of rebleeding, such as spot sign.
10. Platelet count \<100,000/mL; INR \>1.4.
11. Any irreversible coagulation disorders (e.g., hemophilia, von Willebrand disease, use of anticoagulants such as warfarin) or known clotting disorders (e.g., hypercoagulable states).
12. 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.).
13. 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 30-day period.
14. 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.
15. Internal bleeding involving the retroperitoneal, gastrointestinal, or genitourinary system, or respiratory tract bleeding.
16. 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.
17. Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization.
18. Allergy/sensitivity to TNK.
19. Prior enrollment in the study.
20. 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.
21. 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.
22. 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.
23. Patients with mechanical heart valves are excluded. The presence of bioprosthetic valve(s) is permissible.
24. 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.
25. 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.
26. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
27. Patients deemed by the investigator to have unstable conditions that may benefit from other treatments.
28. Patients requesting conservative treatment or standard craniotomy microsurgery treatment.
29. The subject or their legal guardian/representative demonstrates an inability or lack of willingness to provide written informed consent.

Primary outcomes:
measure: Modified Rankin Scale (mRS) score of 0-3 at 180 days.
timeFrame: 180 ±14 days
Secondary outcomes:
measure: Dichotomized eGOS (extended Glasgow Outcome Scale) score at 180 days: 4-8 (good) vs. 1-3(poor)
timeFrame: 180 ± 14 days
measure: All-cause death at 180 days
timeFrame: 180 ± 14 days
measure: Dichotomized, modified Rankin Scale (mRS) Score 0-3 vs. 4-6 at 90 days.
timeFrame: 90 ± 7 days
measure: Dichotomized graded modified Rankin Scale (mRS) score at 180 days : 0-2 vs. 3-6.
timeFrame: 180 ± 14 days
measure: Ordinal graded modified Rankin Scale (mRS) score (0-6) at 180 days.
timeFrame: 180 ± 14 days
measure: Barthel Index (BI) assessment at 180 days.
timeFrame: 180 ±14 days.
measure: Extended Glasgow Outcome (eGOS) assessment at 180 days.
timeFrame: 180 ± 14 days
measure: The change of the National Institutes of Health Stroke Scale (NIHSS) at 5-7 days or discharge if earlier from baseline.
timeFrame: 5-7 days
measure: Safety/Mortality - All-cause death at 30 days
timeFrame: Within 30 days.
measure: Safety/Mortality - All-cause death at 7 days
timeFrame: Within 7 days
measure: Safety/Mortality - Symptomatic rebleeding within 6 days
timeFrame: Within 6 days
measure: Safety/Mortality - Intracranial bacterial infection within 30 days
timeFrame: Within 30 days
measure: Safety/Mortality - Total Adverse Events (AEs) within 30 and 180 days
timeFrame: Within 30 and 180 days
measure: Safety/Mortality - Total Serious Adverse Events (SAEs) within 30 and 180 days
timeFrame: Within 30 and 180 days
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
Study officials:
affiliation: Beijing Tiantan Hospital
name: Yong Cao
role: PRINCIPAL_INVESTIGATOR
References: