Clinical trial NCT06284642: Early Lumbar Drainage Combined With Intrathecal Urokinase Injection for Treatment of Severe Aneurysmal SAH (LD-ITUK)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Aneurysmal Subarachnoid Hemorrhage
Lead sponsor: Second Affiliated Hospital of Nanchang University
Sponsor class: OTHER
Collaborators: name: Changhai Hospital
First posted: 2024-02-29
Enrollment: 424
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: 180 days
Secondary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: 90 days
measure: Relative Modified Rankin Scale (mRS)
timeFrame: 90 days, 180 days
measure: Modified Rankin Scale (mRS) distribution
timeFrame: 180 days
measure: Glasgow Outcome Scale (GOS）
timeFrame: 180 days
measure: Questionnaire EuroQol Five Dimensions Questionnaire (EQ-5D)
timeFrame: 180 days
measure: Barthel Index for Activities of Daily Living (BI)
timeFrame: 180 days
measure: Total hospitalized time
timeFrame: Discharge (assessed up to 30 days)
measure: Total hospitalized costs
timeFrame: Discharge (assessed up to 30 days)
measure: Cerebral vasospasm (CV)
timeFrame: 14 days
measure: Delayed cerebral ischemia (DCI)
timeFrame: 14 days
measure: Death
timeFrame: 180 days
measure: Hydrocephalus
timeFrame: 180 days
measure: Rebleeding
timeFrame: 30 days
Other outcomes:
measure: Subarachnoid hemorrhage volume clearance
timeFrame: 30 days
measure: Correlationship between cerebralspinal fluid pressure with subarachnoid hemorrhage volume
timeFrame: 72 hours after-onset
measure: Correlationship between clinical grades and subarachnoid hemorrhage volume
timeFrame: 72 hours after-onset
Locations:
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University
state: Jiangxi
Study officials:
affiliation: Second Affiliated Hospital of Nanchang University
name: Xingen Zhu, MS
role: PRINCIPAL_INVESTIGATOR
References: