Early Lumbar Drainage Combined With Intrathecal Urokinase Injection for Treatment of Severe Aneurysmal SAH (LD-ITUK)

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

Official title:

Effectiveness and Safety of Early Lumbar Drainage Combined With Intrathecal Urokinase Injection in the Treatment of Severe Aneurysmal Subarachnoid Hemorrhage (LD-ITUK): a Multicentral Randomized Control Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06284642
• Other study ID #: LD-ITUK-2024-001
• Status: Recruiting
• Phase: Phase 4
• Start date: March 28, 2024
• Est. completion date: June 30, 2026

Study information

• Verified date: December 2023
• Source: Second Affiliated Hospital of Nanchang University
• Contact: Xingen Zhu, MS
• Phone: 13803546020
• Email: zxg2008vip[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The LD-ITUK is a multicenter, prospective, randomized, double-blind, blind endpoint, placebo-control design trial. All eligible patients with the diagnosis of severe aSAH will be randomly assigned to the treatment group or the placebo group. Patients in the treatment group will receive standard treatment with the addition of lumbar drainage combined with intrathecal urokinase injection started within 24 hours after aneurysm treatment with 30000 IU urokinase, once a day for 3 consecutive days. Patients in the control group will receive standard treatment with the addition of lumbar drainage combined with intrathecal placebo (0.9%NaCl) injection. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 2 on the modified Rankin Scale (mRS), at 6 months after aneurysmal SAH. Primary outcome will be determined by a member of the Independent Committee on Terminal events.

Description:

Aneurysmal subarachnoid hemorrhages (aSAH) represent about 8% of all strokes and 9.8 per 100,000 per year in China, which is higher than the overall annual incidence rate worldwide. The cumulative death rate after-onset represent about 24.6% in China, only about 30% survivors will be able to have a good neurological prognosis, the majority of the remaining survivors suffer from long-term disability or cognitive impairment. However, these condition may be even worse in patients with severe aSAH. Studies suggest that early clearance of subarachnoid clot may be associated with a good neurological prognosis. Indeed, subarachnoid clot aggravate the phenomena of cerebral vasospasm and delayed cerebral ischemia in the delayed phase, and promote cell injure within the hypoperfusion zone of the brain in the longer term. Thus, early removal of subarachnoid clot may have a favorable effect on neurological prognosis. Current aSAH recommendations and guidelines advocate the use of lumbar drainage only in case of acute hydrocephalus. The EARLYDRAIN trial suggests that lumber cerebrospinal fluid drainage can early remove subarachnoid clot compare to the standard neurocritical treatment, and improve the prognosis after aSAH. However, the ratio of unfavorable prognosis in severe aSAH is still high. Intrathecal urokinase injection has been proved to effeciently remove the subarachnoid clot, however, no randomized control trials have been conducted to evaluate the improvement of lumbar drainage combined with intrathecal urokinase injection in the favorable functional outcome, defined as a score of 0 to 2 on the modified Rankin Scale (mRS), at 6 months after aneurysmal SAH. The LD-ITUK trial was designed to evaluate whether severe aSAH treated by standard treatment with the addition of lumbar drainage combined with intrathecal urokinase injection have a significantly higher percentage of favourable outcome after six months (score 0-2 on the Modified Rankin Scale) compared to the placebo treated by standard treatment with the addition of lumbar drainage combined with intrathecal placebo (0.9%NaCl) injection.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 424
• Est. completion date: June 30, 2026
• Est. primary completion date: January 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient's age = 18 years
• First occurrence of aneurysmal subarachnoid hemorrhage
• Patients without any craniotomy treatment before onset
• Hunt-Hess grade III-V
• mRS grade 0 or 1 before onset
• Aneurysm treatment within 48 hours of onset
• Informed consent given by the subject or guardian

Exclusion Criteria:

• Subarachnoid hemorrhage caused by arteriovenous malformation or moyamoya disease or other cerebrovascular disease
• Patients requiring craniotomy to remove intracranial hematoma
• modified Fisher Scale grade 0
• Prothrombin time (PT) and activated partial thromboplastin time (APTT) are greater than 2 times the extended range
• Absolute contraindications for lumbar puncture (e.g., brain hernia, puncture site infection)
• Patients with a life expectancy of less than 1 year due to other causes
• Other concomitant serious diseases that are difficult to treat;
• Pregnant woman
• Patients who were known to be allergic to urokinase and excipients or had a history of severe allergy and were deemed unsuitable for inclusion by the investigators
• Participated in another interventional clinical trial within 30 days before randomization
• Other reasons deemed unsuitable for study participation by the investigator

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

Drug:
• Urokinase
On the basis of standard treatment for severe neurological conditions, within 24 hours of aneurysm treatment, lumbar drainage combined with intrathecal urokinase injection was started. 30,000 IU urokinase dissolved in 3 ml normal saline was injected into the subarachnoid space, 3 ml normal saline was rinsed into the tube, and the tube was clamped for observation for 2 hours, once a day, for 3 consecutive days. Lumbar cisternae drainage Cerebrospinal fluid is slowly and steadily drained at a rate of less than 8ml/h per hour, the daily drainage volume is not more than 200 ml, and the drainage time of lumbar cisternae is controlled within 7 to 10 days, not more than 14 days.
• Placebo
On the basis of standard treatment for severe neurological conditions, the treatment of lumbar drainage combined with intrathecal placebo saline injection was started within 24 hours after aneurysm treatment, 3 ml placebo was injected into the subarachnoid space, 3 ml normal saline was flushed into the tube, and the tube was observed for 2 hours, once a day for 3 consecutive days. Lumbar cisternae drainage Cerebrospinal fluid is slowly and steadily drained at a rate of less than 8ml/h per hour, the daily drainage volume is not more than 200 ml, and the drainage time of lumbar cisternae is controlled within 7 to 10 days, not more than 14 days.

Locations

Country	Name	City	State
China	The Second Affiliated Hospital of Nanchang University	Nanchang	Jiangxi

Sponsors (2)

Lead Sponsor	Collaborator
Second Affiliated Hospital of Nanchang University	Changhai Hospital

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Subarachnoid hemorrhage volume clearance	dynamic clearance of subarachnoid hemorrhage volume on non-contrast CT scans ofter-onset to discharge	30 days
Other	Correlationship between cerebralspinal fluid pressure with subarachnoid hemorrhage volume	correlationship between admission cerebralspinal fluid pressure with subarachnoid hemorrhage volume	72 hours after-onset
Other	Correlationship between clinical grades and subarachnoid hemorrhage volume	correlationship between Hunt-Hess grade, WFNS, modified Fisher scale with subarachnoid hemorrhage volume	72 hours after-onset
Primary	Modified Rankin Scale (mRS)	Good (mRS 0-2) and Poor (mRS 3-6)	180 days
Secondary	Modified Rankin Scale (mRS)	Good (mRS 0-2) and Poor (mRS 3-6)	90 days
Secondary	Relative Modified Rankin Scale (mRS)	Good (mRS 0-3) and Poor (mRS 4-6)	90 days, 180 days
Secondary	Modified Rankin Scale (mRS) distribution	On the distributed proportion in scores (0-6) on the mRS	180 days
Secondary	Glasgow Outcome Scale (GOS)	Good (GOS 4-5) and Poor (GOS 1-3)	180 days
Secondary	Questionnaire EuroQol Five Dimensions Questionnaire (EQ-5D)	EQ-5D questionnaires have 5 dimensions: "Mobility", "Human Autonomy," "Current Activities", "Pain / Discomfort", "Anxiety / Depression" and all dimensions are described by 3 problem levels corresponding to patient response choices.	180 days
Secondary	Barthel Index for Activities of Daily Living (BI)	The Barthel Index (BI) measures the extent to which somebody can function independently and has mobility in their activities of daily living (ADL) i.e. feeding, bathing, grooming, dressing, bowel control, bladder control, toileting, chair transfer, ambulation and stair climbing.	180 days
Secondary	Total hospitalized time	Toal hospitalized time from ofter-onset to discharge, including neurocritical care unit	Discharge (assessed up to 30 days)
Secondary	Total hospitalized costs	Toal hospitalized costs from ofter-onset to discharge	Discharge (assessed up to 30 days)
Secondary	Cerebral vasospasm (CV)	Occurence of any symptomatic or image CV after aSAH	14 days
Secondary	Delayed cerebral ischemia (DCI)	Occurence of any symptomatic or image DCI after aSAH	14 days
Secondary	Death	Occurence of any death during follow-up after operation	180 days
Secondary	Hydrocephalus	Occurence of a hydrocephalus after-onset	180 days
Secondary	Rebleeding	Occurence of a rebleeding after-onset	30 days