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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Drug-related rebleeding events:
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years and <80 years.
- •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.
- •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.).
- •Glasgow Coma Scale (GCS) score of 5-
- •Stability CT scan done at least 6 hours after diagnostic CT showing clot stability (growth <5 mL as measured by ABC/2 method).
- •Neuronavigation-assisted stereotactic MIPS should be performed within 6 to 24 hours after the diagnostic CT.
- •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.
排除标准
- •Lobar or subtentorial hemorrhage, including posterior fossa hemorrhage and cerebellar hemorrhage.
- •Stability CT scan done at least 6 hours after diagnostic CT showing clot instability (growth ≥5 mL as measured by ABC/2 method).
- •Intraventricular hemorrhage necessitating intervention to address mass effect or midline shift attributable to trapped ventricle syndrome secondary to intraventricular hemorrhage (IVH)-related casting.
- •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.
- •Patients presenting with an unstable intracranial mass or progressive intracranial compartment syndrome.
- •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.
- •Irreversible impairment of brainstem function, characterized by bilateral fixed and dilated pupils, extensor motor posturing, and a Glasgow Coma Scale (GCS) score of ≤
- •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.
- •CT evidence suggesting a high risk of rebleeding, such as spot sign.
- •Platelet count <100,000/mL; INR >1.
- •Any irreversible coagulation disorders (e.g., hemophilia, von Willebrand disease, use of anticoagulants such as warfarin) or known clotting disorders (e.g., hypercoagulable states).
- •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.).
- •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.
- •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.
- •Internal bleeding involving the retroperitoneal, gastrointestinal, or genitourinary system, or respiratory tract bleeding.
- •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.
- •Positive urine or serum pregnancy test in pre-menopausal female subjects without a documented history of surgical sterilization.
- •Allergy/sensitivity to TNK.
- •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.
- •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.
- •Patients with mechanical heart valves are excluded. The presence of bioprosthetic valve(s) is permissible.
- •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.
- •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.
- •Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
- •Patients deemed by the investigator to have unstable conditions that may benefit from other treatments.
- •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.
研究组 & 干预措施
Teneplase assisted dissolution of blood clot therapy
After CT reexamination 6 hours after surgery, the calculated injection amount of teneplase (teneplase injection amount = volume of hematoma × concentration of ascending drug) was diluted to 1ml with sterile injection water, and injected into the stereotaxically planned puncture path according to the location and size of the hematoma in turn. 0.5ml normal saline was used to flush the pipeline, and the drainage tube was fixed and closed for 2 hours. After the medication has fully acted with the hematoma mass, the drainage tube is re-opened to allow gravity drainage. CT examination was performed at 24 hours, 48 hours, 72 hours and 96 hours. Continuation or termination of the trial based on CT results at 24 hours, 48 hours, 72 hours, 96 hours: Teneplase was discontinued when the surgical goal defined by the test was achieved (residual hematoma ≤10ml), or new blood events occurred (compared with the previous time point CT, a CT value of > 72Hu and a volume of > 6ml of the space found in an
干预措施: Minimally invasive surgery plus low-dose rhTNK-tPA group (Drug)
Teneplase assisted dissolution of blood clot therapy
After CT reexamination 6 hours after surgery, the calculated injection amount of teneplase (teneplase injection amount = volume of hematoma × concentration of ascending drug) was diluted to 1ml with sterile injection water, and injected into the stereotaxically planned puncture path according to the location and size of the hematoma in turn. 0.5ml normal saline was used to flush the pipeline, and the drainage tube was fixed and closed for 2 hours. After the medication has fully acted with the hematoma mass, the drainage tube is re-opened to allow gravity drainage. CT examination was performed at 24 hours, 48 hours, 72 hours and 96 hours. Continuation or termination of the trial based on CT results at 24 hours, 48 hours, 72 hours, 96 hours: Teneplase was discontinued when the surgical goal defined by the test was achieved (residual hematoma ≤10ml), or new blood events occurred (compared with the previous time point CT, a CT value of > 72Hu and a volume of > 6ml of the space found in an
干预措施: Minimally invasive surgery plus medium dose rhTNK-tPA group (Drug)
Teneplase assisted dissolution of blood clot therapy
After CT reexamination 6 hours after surgery, the calculated injection amount of teneplase (teneplase injection amount = volume of hematoma × concentration of ascending drug) was diluted to 1ml with sterile injection water, and injected into the stereotaxically planned puncture path according to the location and size of the hematoma in turn. 0.5ml normal saline was used to flush the pipeline, and the drainage tube was fixed and closed for 2 hours. After the medication has fully acted with the hematoma mass, the drainage tube is re-opened to allow gravity drainage. CT examination was performed at 24 hours, 48 hours, 72 hours and 96 hours. Continuation or termination of the trial based on CT results at 24 hours, 48 hours, 72 hours, 96 hours: Teneplase was discontinued when the surgical goal defined by the test was achieved (residual hematoma ≤10ml), or new blood events occurred (compared with the previous time point CT, a CT value of > 72Hu and a volume of > 6ml of the space found in an
干预措施: Minimally invasive surgery plus high dose rhTNK-tPA group (Drug)
结局指标
主要结局
Drug-related rebleeding events:
时间窗: Within 24 hours of the last dose
CT examinations were performed at 24, 48, 72, and 96 hours after administration. Compared with the CT at the previous time point, a CT value of more than 72 HU and a volume of more than 5 ml found in and around the hematoma cavity were defined as newly emitted blood.
次要结局
未报告次要终点
研究者
Dr. Yong Cao
deputy director
Beijing Tiantan Hospital