Clinical trial NCT06668441: Minimally Invasive Surgery and RhTNK-tPA for Intracerebral Hemorrhage Evacuation
Official title: A Phase I Pilot Clinical Trial of TNK Tissue-type Plasminogen Activator (rhTNK-tPA) Dose Escalation for Hypertension-Induced Intracerebral Hemorrhage Using Stereotactic Aspiration Technique to Remove the Hematoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Intracranial Hemorrhages
Cerebrovascular Disorders
Cerebral Hemorrhage
Hemorrhage
Keywords: Basal ganglia
Stereotactic puncture therapy
Cerebral Hemorrhage
rhTNK-tPA
Minimally Invasive Surgery
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
First posted: 2024-10-31
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to determine the safety of using a combination of robot-assisted stereotactic puncture and clot lysis with rhTNK-tPA to remove intracerebral hemorrhage (ICH) and to provide dose evidence for a phase III clinical trial.

Detailed description: Minimally invasive puncture surgery (MIPS) is a recommended effective surgical treatment method by the new guidelines to improve the mortality rate of intracerebral hemorrhage patients. It is easy to operate and has the conditions for widespread implementation. Stereotactic puncture is the least invasive treatment method, which can reduce the effect of hematoma occlusion and cytotoxicity and maximize the protection of neurological function. The MISTIE III study published in The Lancet showed that the mortality rate of the group treated with minimally invasive intracerebral hematoma evacuation combined with alteplase was reduced at 365 days, but the functional prognosis was not improved. Alteplase may have poor fibrin specificity, a short half-life, and a weak effect on PAI-1, resulting in incomplete blood clot dissolution, which may be the reason for poor prognosis. Tenecteplase (rhTNK-tPA), a third-generation specific fibrinolytic agent, is used for intravenous thrombolysis in acute ischemic stroke and has higher fibrin specifc. The study design is an open-label, non-comparative, phase 1 dose escalation protocol.The purpose of this trial is to determine the safety of using a combination of robot-assisted stereotactic puncture and clot lysis with rhTNK-tPA to remove intracerebral hemorrhage (ICH) and to provide dose evidence for a phase III clinical trial.

Eligibility criteria: Inclusion Criteria:

1. Age ≥18 years and \<80 years.
2. Symptoms must have manifested within 24 hours prior to the diagnostic CT 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. Neuronavigation-assisted stereotactic MIPS should be performed 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 enrollment time point.

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. 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.
20. 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.
21. Patients with mechanical heart valves are excluded. The presence of bioprosthetic valve(s) is permissible.
22. 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.
23. 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.
24. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
25. Patients deemed by the investigator to have unstable conditions that may benefit from other treatments.
26. Patients requesting conservative treatment or standard craniotomy microsurgery treatment.

The subject or their legal guardian/representative demonstrates an inability or lack of willingness to provide written informed consent.

Primary outcomes:
measure: Drug-related rebleeding events:
timeFrame: Within 24 hours of the last dose
Secondary outcomes:
Other outcomes:
Locations:
city: Beijing
country: China
facility: : Beijing Tongren Hospital, Capital Medical University,
state: Beijing
Study officials:
affiliation: Beijing Tiantan Hospital
name: Yong Cao, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhou X, Chen J, Li Q, Ren G, Yao G, Liu M, Dong Q, Guo J, Li L, Guo J, Xie P. Minimally invasive surgery for spontaneous supratentorial intracerebral hemorrhage: a meta-analysis of randomized controlled trials. Stroke. 2012 Nov;43(11):2923-30. doi: 10.1161/STROKEAHA.112.667535. Epub 2012 Sep 18.
citation: Wang WZ, Jiang B, Liu HM, Li D, Lu CZ, Zhao YD, Sander JW. Minimally invasive craniopuncture therapy vs. conservative treatment for spontaneous intracerebral hemorrhage: results from a randomized clinical trial in China. Int J Stroke. 2009 Feb;4(1):11-6. doi: 10.1111/j.1747-4949.2009.00239.x.
citation: Scaggiante J, Zhang X, Mocco J, Kellner CP. Minimally Invasive Surgery for Intracerebral Hemorrhage. Stroke. 2018 Nov;49(11):2612-2620. doi: 10.1161/STROKEAHA.118.020688.
citation: Li M, Mu F, Su D, Han Q, Guo Z, Chen T. Different surgical interventions for patients with spontaneous supratentorial intracranial hemorrhage: A network meta-analysis. Clin Neurol Neurosurg. 2020 Jan;188:105617. doi: 10.1016/j.clineuro.2019.105617. Epub 2019 Nov 20.
citation: Hanley DF, Thompson RE, Rosenblum M, Yenokyan G, Lane K, McBee N, Mayo SW, Bistran-Hall AJ, Gandhi D, Mould WA, Ullman N, Ali H, Carhuapoma JR, Kase CS, Lees KR, Dawson J, Wilson A, Betz JF, Sugar EA, Hao Y, Avadhani R, Caron JL, Harrigan MR, Carlson AP, Bulters D, LeDoux D, Huang J, Cobb C, Gupta G, Kitagawa R, Chicoine MR, Patel H, Dodd R, Camarata PJ, Wolfe S, Stadnik A, Money PL, Mitchell P, Sarabia R, Harnof S, Barzo P, Unterberg A, Teitelbaum JS, Wang W, Anderson CS, Mendelow AD, Gregson B, Janis S, Vespa P, Ziai W, Zuccarello M, Awad IA; MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019 Mar 9;393(10175):1021-1032. doi: 10.1016/S0140-6736(19)30195-3. Epub 2019 Feb 7.
citation: Guo G, Pan C, Guo W, Bai S, Nie H, Feng Y, Li G, Deng H, Ma Y, Zhu S, Tang Z. Efficacy and safety of four interventions for spontaneous supratentorial intracerebral hemorrhage: a network meta-analysis. J Neurointerv Surg. 2020 Jun;12(6):598-604. doi: 10.1136/neurintsurg-2019-015362. Epub 2020 Jan 3.