Safety and Efficacy of Stereotactic Aspiration Plus Urokinase in Deep Intracerebral Hemorrhage Evacuation (STAPLE-dICH)

Safety and Efficacy of Stereotactic Aspiration Plus Urokinase in Deep Intracerebral Hemorrhage Evacuation: a Multicentral Randomized, Controlled, Open-label, Trial

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 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.

Study Overview

• Status: Recruiting
• Conditions: Treatment of Spontaneous Intracerebral Hemorrhage
• Intervention / Treatment: Procedure: STAPLE

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. This is a multicentral, randomised, controlled, open-label, trial, which will enroll about 500 deep ICH patients in 20 qualified hospitals all over China. The eligible patients should be treated within 24h after bleeding，without cerebral hernia, but with contralateral hemiplegia and GCS≥9. This study is conducted in 2 steps. The first step is a dose climbing test to determine the safety and optimal dose of urokinase irrigation. One hundred patients will be randomly assigned to five groups (20000 U, 40000 U, 60000 U, 80000 U, 10000 U urokinase/2-3 mL saline solution) with a block size of 10 patients. Participants within a block will be assigned equally (2:2:2:2:2) to the five dosage groups. Primary outcomes are safety outcomes: 30-day mortality, 7-day procedure-related mortality, 72 h symptomatic bleeding, and 30-day brain infections. The second step is to validate whether STAPLE ( using the optimal dose determined in step one) is superior to conservative treatment in improving long-term outcomes (1 year) in early (within 24h), non-hernia, contralateral limb hemiplegic dICH patients. Four hundred participants will be randomly allocated by local site personnel using a central web-based interactive response system. Block randomization (size =4) is performed, and participants within a block are assigned equally (2:2) to STAPLE group and Conservative treatment group. Three stratification factors are considered including age (40-64 years versus 65-85 years), initial ICH volume (25-44 ml versus 45-65 ml) and GCS (9-12 scores versus 13-15 scores). Primary outcome is good functional outcome, defined as the proportion ofpatients who achieve a modified Rankin Scale (mRS) score of 0-3 at 1 year after hemorrhage. Analysis of the primary efficacy outcome is performed in the modified intention-to-treat (mITT) population, including all eligible, randomly assigned participants who have been subjected to treatment. Clinical data and radiology data will be collected by electric case report form (CRF) and uploaded online by each neurosurgery center to form the prospective clinical database in First Affiliated Hospital of Fujian Medical University. This RCT study will be across a 3-year period with a 2 years interval of enrollment and 1 year follow up for each patient.

• Study Type: Interventional
• Enrollment (Anticipated): 500
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Lin Fuxin, PHD,MD; Phone Number: +86 13552358381; Email: lfxstuy@126.com
• Study Contact Backup: Name: Kang Dezhi, MD; Phone Number: +86 13859099988; Email: kdz999888@163.com

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China
      • Recruiting
      • First Affiliated Hospital of Fujian Medical University
      • Contact: Lin Fuxin, MD; Phone Number: +86 13552358381; Email: lfxstudy@126.com
      • Principal Investigator: Kang Dezhi, PHD,MD
      • Sub-Investigator: Lin Fuxin, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 75 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with a deep spontaneous intracerebral hemorrhage on emergent CT scan (≥1 cm from the cortical surface), but without hydrocephalus caused by intraventricular hemorrhage.
• Patients with an age of 14-75 years old and have a mRS of 0-1 before ICH.
• Patients with a clot volume between 25 and 65ml, measured by the ABC/2 method.
• Patients without cerebral herniation and the benefit of surgeical treatment is unknown.
• The time from the ICH attack to the randomization is within 24 hours.
• Patients with motor deficits and the GCS of 9-15.
• Patients with written informed consent, and will accept long-term follow-up.

Exclusion Criteria:

• ICH is caused by aneurysms, arteriovenous malformations, tumor or trauma.
• Patients have a history of intracerebral hemorrhage or ischemic cerebral infarction and are disabled.
• Patients have severe underlying diseases, which may affect the outcomes.
• Patients have severe coagulation disorders with INR ≥ 1.5.
• Pregnant and lactating patients.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: STAPLE group; 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.	Procedure: STAPLE; Stereotactic aspiration plus urokinase clot irrigation
NO_INTERVENTION: Conservative treatment group; We used the 2015 ASA/AHA and 2020 Chinese multidisciplinary expert consensus recommendations for treatment of spontaneous intracerebral hemorrhage, including a standard approach to monitoring patients' airways, ventilation, intracranial pressure, sedation, and pharmacological treatment of intracranial mass effect. Patients allocated to the standard medical care group had follow-up CT scans and other monitoring assessments on the same schedule as those in the STAPLE group. Conventional craniotomy and hematoma evacuation can be performed when cerebral hernia or rebleeding happened.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
7-day procedure-related mortality	7-day procedure-related mortality	Within post-operative seventh day
30-day all-cause mortality	30-day all-cause mortality	Within post-operative thirtith day
30-day symptomatic re-hemorrhage	30-day symptomatic re-hemorrhage	Within post-operative thirtith day
30-day brain infections	30-day brain infections	Within post-operative thirtith day

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Fujian Medical University
• Collaborators: LanZhou University; Shaanxi Provincial People's Hospital; Fifth Affiliated Hospital of Zhengzhou University; The Second Hospital of Shandong University; Longyan City First Hospital; Tangshan Gongren Hospital; Qilu Hospital of Shandong University (Qingdao); Qingyuan People's Hospital; Department of Science and Technology of Fujian province; Shishi General Hospital; Wuping County Hospital; Fuqing Municipal Hospital; Jinjiang Municipal Hospital; Huian County Hospital; Anxi County Hospital; The Second Hospital of Sanming; Pucheng County Hospital; Nanan Hospital; MinDong Hospital of Ningde City; Affiliated Hospital of Putian University; Lianjiang County Hospital; Shunchang County Hospital
• Investigators: Study Chair: Kang Dezhi, MD., The first affilicated hospital of Fujian Medical univercity

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2020
• Primary Completion (ANTICIPATED): August 31, 2023
• Study Completion (ANTICIPATED): September 30, 2023

Study Registration Dates

• First Submitted: December 23, 2020
• First Submitted That Met QC Criteria: December 23, 2020
• First Posted (ACTUAL): December 29, 2020

Study Record Updates

• Last Update Posted (ACTUAL): December 29, 2020
• Last Update Submitted That Met QC Criteria: December 23, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Long-term outcome; Deep-Seated Spontaneous Intracerebral Hemorrhage; Stereotactic Aspiration; Urokinase Irrigation
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: 2019Y9304

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We will share individual participant data after the primary results have been published.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No