Clinical trial NCT04686877: Safety and Efficacy of Stereotactic Aspiration Plus Urokinase in Deep Intracerebral Hemorrhage Evacuation
Official title: Safety and Efficacy of Stereotactic Aspiration Plus Urokinase in Deep Intracerebral Hemorrhage Evacuation: a Multicentral Randomized, Controlled, Open-label, Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Treatment of Spontaneous Intracerebral Hemorrhage
Keywords: Deep-Seated Spontaneous Intracerebral Hemorrhage
Stereotactic Aspiration
Urokinase Irrigation
Randomized Controlled Trial
Long-term outcome
Lead sponsor: First Affiliated Hospital of Fujian Medical University
Sponsor class: OTHER
Collaborators: name: Department of Science and Technology of Fujian province
name: Longyan City First Hospital
name: Fifth Affiliated Hospital of Zhengzhou University
name: Shanxi Provincial People's Hospital
name: Tangshan Gongren Hospital
name: Lanzhou University Second Hospital
name: Qilu Hospital of Shandong University (Qingdao)
name: The Second Hospital of Shandong University
name: Shishi General Hospital
name: Wuping County Hospital
name: Fuqing Municipal Hospital
name: Qingyuan People's Hospital
name: Jinjiang Municipal Hospital
name: Anxi County Hospital
name: Nanan Hospital
name: MinDong Hospital of Ningde City
name: Affiliated Hospital of Putian University
name: Lianjiang County Hospital
name: Shunchang County Hospital
name: Yulin No.2 Hospital
name: The First Affiliated Hospital of Xiamen University
name: The Second Affiliated Hospital of Xiamen Medical College
name: Zhangzhou Municipal Hospital of Fujian Province
name: Longyan People's Hospital of Fujian Province
First posted: 2020-12-29
Enrollment: 400
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A surgical intervention model of stereotactic hematoma punctural catheter placement, drainage and urokinase irrigation in spontaneous intracerebral hemorrhage.
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion criteria:

1. aged 40 years or older;
2. the duration from onset to the baseline computed tomography angiography (CTA) scan was between 6 to 24 hours;
3. patients with a spontaneous ICH in the deep brain parenchyma (≥1 cm from the cortical surface); with hematoma volume more than 25 ml (measured with the ABC/2 method); without hydrocephalus caused by intraventricular hemorrhage; without cerebral herniation and the benefit of surgical treatment was unknown;
4. The Glasgow Coma Scale (GCS) ranged from 9 to 15;
5. patients with motor deficits;
6. The modified Rankin Score (mRS) ranged from 0 to1 before onset.

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.

Primary outcomes:
measure: Good functional outcome, measured by the modified Rankin Scale (mRS)
timeFrame: At day 365 after randomization
Secondary outcomes:
measure: Proportion of hematoma evacuation by craniotomy or decompressive hemicraniectomy
timeFrame: at 1 year after randomization
measure: Residual hematoma volume
timeFrame: At day 7 after randomization in the Conservative Treatment group; At 72 hours after the last urokinase infusion in the STAPLE group
measure: All-cause mortality
timeFrame: At 365 days after randomization
Other outcomes:
Locations:
city: Fuzhou
country: China
facility: First Affiliated Hospital of Fujian Medical University
state: Fujian
Study officials:
affiliation: The first affilicated hospital of Fujian Medical univercity
name: Kang Dezhi, MD.
role: STUDY_CHAIR
References: