Safety and Efficacy of Stereotactic Aspiration Plus Urokinase in Deep Intracerebral Hemorrhage Evacuation

Not Applicable

Recruiting

• Conditions: Treatment of Spontaneous Intracerebral Hemorrhage
• Interventions: Procedure: STAPLE

• Registration Number: NCT04686877
• Lead Sponsor: First Affiliated Hospital of Fujian Medical University

Brief Summary

This is a nationwide, multicenter, open-label, randomized controlled trial of early minimally invasive treatment for deep-seated spontaneous cerebral hemorrhage (dICH). The study consists of 2 steps: the first step is to conduct a dose climbing test to determine the safety and optimal dose of urokinase intra-hematoma irrigation after stereotactic aspiration; the second step is to validate whether stereotactic aspiration plus urokinase irrigation (the optimal dose determined in step one) is superior to conservative treatment in improving long-term outcomes (1 year) in early (within 24h) dICH patients.

Detailed Description

Surgical options have been repeatedly evaluated in large multicenter randomized controlled trials that unfortunately have not demonstrated improved outcomes. Recently, MISTIE III study concluded that minimally invasive surgery with thrombolysis was safely adopted by doctors, but did not improve the proportion of patients who achieved a good long-term outcome. However, subgroup analyses of MISTIE cohorts showed that patients with GCS≥9, time from stroke to treatment initiation \<36 h, and reduction of ICH to ≤15 mL had a higher likelihood of achieving mRS of 0 to 3. Thus, we designed this study, considering the reality of clinical practice in China and the limitations of previous studies, to determine the optimal dose and safety of urokinase intra-hematoma irrigation, and to validate whether stereotactic aspiration plus urokinase irrigation (STAPLE) is superior to conservative treatment in improving long-term outcomes (1 year) in early (within 24h) dICH patients.

The Part A study aimed to find the safe optimal dose of urokinase by a Utility-based Bayesian optimal interval (U-BOIN) phase I/II design. In this design, the dose-limiting toxicity (DLT) is defined as rebleeding that occurred from the first urokinase injection to 72 h after the last injection. And the effective performance is defined as a hematoma volume \<10 ml on CT scan after the last injection as well as the total number of injections not exceeding four. he demographic data, medical history, examination results, complications, treatment, and survival information of the participants are recorded during hospitalization. The participants should go to the outpatient clinic on the 30th day after entering the study, and their CT scan and neurological examination results will be recorded. If the participants died, the time and cause of death will be collected. In the Part B study, eligible patients will be randomized in equal proportions between STAPLE group and conservative treatment group immediately after the pre-surgical CTA. The method of block randomization and stratification control is used. Patients in the STAPLE group receive the stereotactic CTA-guided aspiration and drainage within 36h after symptoms onset, and the injection volume of urokinase was determined according to the results of CT examination at 6 hours after operation. Patients in the conservative treatment group are treated routinely according to the Guidelines for the Management of Spontaneous Intracerebral Hemorrhage (AHA/ASA, 2015). Hematoma evacuation by craniotomy or decompressive hemicraniectomy is considered in deteriorating patients as a life-saving measure. Subjects will be followed up by phone at days 90, 180, and 270. And the survivors should go to the outpatient clinic of the participating centers at day 30 and day 365 after randomization. Their CT results and neurological physical examination (including but not limited to mRS, Glasgow Outcome Score (GOS), and Barthel Index (BI)) will be recorded.

Study Timeline

• Study First Submitted: 2020-12-23
• Study First Submitted QC: 2020-12-23
• Study First Posted: 2020-12-29
• Study Start: 2021-01-31
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-08
• Last Update Posted: 2025-02-12
• Primary Completion: 2025-08-31
• Study Completion: 2025-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

Not provided

Exclusion Criteria

1. ICH was caused by aneurysms, arteriovenous malformations, tumors, or trauma;
2. patients had a history of intracerebral hemorrhage or ischemic cerebral infarction;
3. patients had severe coagulation disorders with INR ≥ 1.5;
4. patients had severe underlying diseases, which may affect the outcomes;
5. pregnant and lactating patients;
6. patients refused to sign the informed consent and receive follow-up.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
STAPLE group	STAPLE	For patients in STAPLE group, intracranial hematoma will be removed by intraoperative stereotactic computer tomography-guided aspiration followed by urokinase clot irrigation (every 12 h for up to 5 days or until reduction of ICH to ≤10 mL). CT will be performed before operation in all the patients for intraoperative navigation, and the minimally invasive surgery will be performed within 24 hours after intracerebral hemorrhage onset. On the 1st, 3rd, 5th, and 7th day of post-operation, patients will be re-examined using CT. Conventional craniotomy and hematoma evacuation can be performed when cerebral hernia or rebleeding happened.

Primary Outcome Measures

Name	Time	Method
Good functional outcome, measured by the modified Rankin Scale (mRS)	At day 365 after randomization	Good functional outcome is defined as a mRS of ≤3 points and will be assessed as binary outcome (yes/no, final value). In this context, a mRS score of 3 points reflects the ability to walk unassisted and care for one's own bodily needs despite being moderately dependent on assistance, while a mRS score of 4 points describes a patient who is not able to walk anymore and needs assistance with all daily activities and thus marks a severe loss of patient autonomy.

Secondary Outcome Measures

Name	Time	Method
Residual hematoma volume	At day 7 after randomization in the Conservative Treatment group; At 72 hours after the last urokinase infusion in the STAPLE group	Proportion of patients with hematoma volume reduced to less than 10mL \[binary outcome (yes/no)\]. The hematoma volume will be measured on cranial computer tomography (cCT) at day 7 after randomization in the Conservative Treatment group and 72 hours after the last urokinase infusion in the STAPLE group.
Proportion of hematoma evacuation by craniotomy or decompressive hemicraniectomy	at 1 year after randomization	Number of participants who were converted to hematoma evacuation by craniotomy or decompressive hemicraniectomy for reasons such as hematoma enlargement after conservative treatment or urokinase treatment.
All-cause mortality	At 365 days after randomization	Mortality rate as measured by death of a participant \[binary outcome (yes/no)\]. Death induced by any cause.

Trial Locations

Locations (2)

First Affiliated Hospital of Fujian Medical University; 🇨🇳 Fuzhou, Fujian, China

First Affiliated Hospital of Fujian Medical University; 🇨🇳 Fuzhou, Fujian, China