rhTNK-tPA Thrombolytic Removal of Intraventricular Hemorrhage

NCT ID: NCT06814964

Last Updated: 2025-02-27

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-01
• Study Completion Date: 2025-06-01

Brief Summary

The purpose of this pilot study is to determine the safety and optimal dose of clot lysis with rhTNK-tPA for intraventricular hemorrhage, using stereotactic guidance for extraventricular drain placement.

Detailed Description

In patients with spontaneous intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH) is often associated with catastrophic outcomes. Studies have reported that the mortality rate in ICH patients with IVH exceeds 50%, and fewer than 20% of survivors achieve good functional outcomes. Hematoma lysis therapy appears to influence both mortality and functional recovery. Previous systematic reviews and meta-analyses suggest that the removal of intraventricular hemorrhage, by alleviating acute obstructive hydrocephalus and reducing neurotoxicity, may improve survival rates and long-term functional outcomes. The CLEAR III trial, published in The Lancet, demonstrated that in patients with IVH and external ventricular drainage, the 180-day mortality rate was lower with intraventricular alteplase lavage compared to saline (0.9%), although functional outcomes did not improve.

Alteplase, a second-generation fibrinolytic agent, facilitates the dissolution of hematomas following intraventricular hemorrhage. However, its low fibrin specificity, short half-life, and weak resistance to plasminogen activator inhibitor type 1 (PAI-1) often necessitate multiple thrombolytic administrations. This may explain the lack of improvement in neurological functional outcomes. In contrast, tenecteplase, a third-generation fibrinolytic agent, exhibits higher fibrin specificity and a longer half-life, which may enhance thrombolytic efficiency and hematoma clearance rates. These properties make tenecteplase a potentially safer and more effective option for hematoma dissolution in patients with intraventricular hemorrhage.

Building on the findings of the CLEAR III trial and previous research, this study aims to replace alteplase with tenecteplase and conduct a prospective, single-center, "3+3" dose-escalation trial to evaluate the safety and optimal dosing of tenecteplase-assisted hematoma dissolution for intraventricular hemorrhage. The results will provide a foundation for future multicenter randomized controlled trials.

Conditions

Intraventricular Hemorrhage

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low dose rhTNK-tPA thrombolytic removal of intraventricular hemorrhage

Low dose tenecteplase (injection amount = volume of intraventricular hematoma × 0.009 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD. At least 4 ml of CSF is removed prior to injection of 1 ml of test article followed by a 3 ml flush of sterile saline into the ventricle. Injection is followed by closure of the catheter for 1 hour and then opening of the EVD for drainage of clot and CSF until the next injection every 12 hours. Treatment continues for up to 8 doses of test article unless, an treatment success endpoint of clot lysis is reached, or an adverse treatment endpoint occurs (e.g. new hemorrhage: compared with the previous time point CT, a CT value of \> 72Hu and a volume of \> 5ml). Treatment success endpoints are (i) both 3rd and 4th ventricles are open; (ii) IVH related mass effect \[dilated or shifted ventricle\] is resolved; or (iii) an estimated 80% resolution of the IVH clot has occurred from the time clot stability was established.

Group Type: EXPERIMENTAL

Low dose group

Intervention Type: DRUG

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.009 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

Medium dose rhTNK-tPA thrombolytic removal of intraventricular hemorrhage

Medium dose tenecteplase (injection amount = volume of intraventricular hematoma × 0.018 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD. At least 4 ml of CSF is removed prior to injection of 1 ml of test article followed by a 3 ml flush of sterile saline into the ventricle. Injection is followed by closure of the catheter for 1 hour and then opening of the EVD for drainage of clot and CSF until the next injection every 12 hours. Treatment continues for up to 8 doses of test article unless, an treatment success endpoint of clot lysis is reached, or an adverse treatment endpoint occurs (e.g. new hemorrhage: compared with the previous time point CT, a CT value of \> 72Hu and a volume of \> 5ml). Treatment success endpoints are (i) both 3rd and 4th ventricles are open; (ii) IVH related mass effect \[dilated or shifted ventricle\] is resolved; or (iii) an estimated 80% resolution of the IVH clot has occurred from the time clot stability was established.

Group Type: EXPERIMENTAL

Medium dose group

Intervention Type: DRUG

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.018 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

High dose rhTNK-tPA thrombolytic removal of intraventricular hemorrhage

High dose tenecteplase (injection amount = volume of intraventricular hematoma × 0.027 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD. At least 4 ml of CSF is removed prior to injection of 1 ml of test article followed by a 3 ml flush of sterile saline into the ventricle. Injection is followed by closure of the catheter for 1 hour and then opening of the EVD for drainage of clot and CSF until the next injection every 12 hours. Treatment continues for up to 8 doses of test article unless, an treatment success endpoint of clot lysis is reached, or an adverse treatment endpoint occurs (e.g. new hemorrhage: compared with the previous time point CT, a CT value of \> 72Hu and a volume of \> 5ml). Treatment success endpoints are (i) both 3rd and 4th ventricles are open; (ii) IVH related mass effect \[dilated or shifted ventricle\] is resolved; or (iii) an estimated 80% resolution of the IVH clot has occurred from the time clot stability was established.

Group Type: EXPERIMENTAL

High dose group

Intervention Type: DRUG

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.027 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

Interventions

Low dose group

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.009 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

Intervention Type: DRUG

Medium dose group

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.018 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

Intervention Type: DRUG

High dose group

The calculated injection amount of tenecteplase (tenecteplase injection amount = volume of intraventricular hematoma × 0.027 mg/ml) was diluted to 1ml with sterile injection water, and administered via the EVD.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age 18-80 years.

2. Symptom onset within 24 hours prior to diagnostic CT scan. Patients with unknown onset time should be excluded. For patients with symptoms occurring during sleep, the time of symptom onset should be considered as the last time the patient was awake and asymptomatic.

3. Spontaneous intracerebral hemorrhage (ICH) ≤ 30 ml，with intraventricular hemorrhage (IVH) >20 ml obstructing the third and/or fourth ventricles.

4. All patients must have an external ventricular drain (EVD) placed prior to enrollment: The EVD should be accurately positioned into the largest cerebrospinal fluid (CSF) pool or the least bloody site in the lateral ventricle using robotic stereotactic guidance.

5. A stability CT scan performed ≥ 6 hours after EVD placement must confirm ICH clot stability: The ICH volume change should be ≤ 5 ml compared to the previous CT scan. If the stability CT scan shows a difference > 5 ml, a repeat stability CT scan should be performed ≥ 12 hours later. Stability CT scans may be repeated every 12 hours within 72 hours of the diagnostic CT scan. If two consecutive CT scans show a hematoma enlargement ≤ 5 ml and the ICH volume remains ≤ 35 ml, the patient is eligible.

6. IVH clot stability: The width of the lateral ventricle most affected by the clot must not increase by > 2 mm. If the stability CT scan shows a difference > 2 mm, a repeat stability CT scan should be performed ≥ 12 hours later. Stability CT scans may be repeated every 12 hours within 72 hours of the diagnostic CT scan. If two consecutive CT scans show a change ≤ 2 mm, the patient is eligible.

7. Catheter tract bleeding on the stability CT scan must be ≤ 5 ml. If any CT slice shows catheter tract bleeding > 5 ml, a repeat stability CT scan should be performed ≥ 12 hours later. Stability CT scans may be repeated every 12 hours within 72 hours of the diagnostic CT scan. If two consecutive CT scans show a change ≤ 5 ml and the total hematoma volume along the tract is ≤ 10 ml, the patient is eligible.

8. On the stability CT scan, the third and/or fourth ventricles must be occluded with blood.

9. Primary IVH (ICH = 0) is eligible.

10. Sustained systolic blood pressure (SBP) < 180 mmHg for at least 6 hours prior to enrollment. (Patients do not need to meet the SBP criteria throughout the screening period, but vital signs should remain stable during the enrollment window).

11. No intraventricular thrombolytic treatment within 12 hours of symptom onset.

12. Enrollment must be completed within 72 hours of the diagnostic CT scan. (The 72-hour limit may be extended with PI approval for reasons such as hematoma stability, INR stability, or other valid justifications).

13. Pre-morbid modified Rankin Scale (mRS) score of 0 or 1.

Exclusion Criteria

1. Hemorrhage caused by aneurysms, arteriovenous malformations (AVM), tumors, or other identifiable causes. If the cause of ICH is unknown, CTA, DSA, or other definitive imaging must be performed during screening to rule out these causes. If imaging is negative, the patient is eligible.

2. Presence of choroid plexus vascular malformation or Moyamoya disease.

3. Hypercoagulable state or coagulopathy. Patients requiring long-term anticoagulation are excluded. Reversal of anticoagulation is permitted if long-term anticoagulation is not required.

4. Use of anticoagulants (e.g., dabigatran, apixaban, rivaroxaban) or antiplatelet agents (e.g., tirofiban, ticagrelor, cilostazol, clopidogrel) within one week prior to symptom onset (aspirin is allowed).

5. Platelet count < 100,000 or INR > 1.4.

6. Pregnancy (positive serum or urine pregnancy test).

7. Infratentorial hemorrhage.

8. Thalamic hemorrhage with significant midbrain extension, third nerve palsy, or dilated and non-reactive pupils. Other supranuclear gaze abnormalities are not excluded. Posterior fossa or cerebellar hemorrhages are excluded.

9. Subarachnoid hemorrhage (SAH) or any atypical hematoma location or appearance on diagnostic CT scan. Angiography (CTA, DSA, or MRA/MRI) must be performed to rule out other causes. If no source of bleeding is identified, the patient is eligible. Cortical SAH secondary to clot lysis is eligible.

10. Unstable ICH/IVH with ongoing hematoma enlargement.

11. Indications for craniotomy: ① Progressive decline in consciousness; ② Signs of brain herniation; ③ Hematoma located < 1 cm from the cortical surface.

12. Ongoing internal bleeding involving retroperitoneal, gastrointestinal, genitourinary, or respiratory tracts. Patients with prior bleeding that is clinically stable for ≥ 12 hours and without coagulopathy or bleeding disorders are eligible.

13. Multifocal superficial bleeding at multiple vascular puncture or access sites (e.g., venipuncture, arterial puncture) or recent surgical sites.

14. Any condition that, in the investigator's opinion, poses a significant risk to the patient or makes the patient unsuitable for the study.

15. Planned or concurrent participation in another interventional clinical trial. Participation in observational, natural history, or epidemiological studies without intervention is allowed.

16. Inability to obtain informed consent from the patient or legal representative.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beijing Tiantan Hospital

OTHER

Sponsor Role: lead

Responsible Party

Dr. Yong Cao

Chief Physician

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Yong Cao

Role: PRINCIPAL_INVESTIGATOR

Beijing Tiantan Hospital

Locations

Beijing Tiantan Hospital

Beijing, Beijing Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Yong Cao

Role: CONTACT

caoyong@bjtth.org

+86 13601362306

Shaozhi Zhao

Role: CONTACT

sdsgzsz@163.com

+86 18801217693

Facility Contacts

Yong Cao

Role: primary

caoyong@bjtth.org

+86 13601362306

Shaozhi Zhao

Role: backup

sdsgzsz@163.com

+86 18801217693

Other Identifiers

rhTNK-tPA-IVH01

Identifier Type: -

Identifier Source: org_study_id