Early Lumbar Drainage Plus Intrathecal Urokinase in Severe Aneurysmal Subarachnoid Hemorrhage (LD-ITUK)

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат 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,

Первичные конечные точки

• Modified Rankin Scale (mRS) [Срок оценки: 180 days]

Вторичные конечные точки (12)

• Modified Rankin Scale (mRS) [Срок оценки: 90 days]
• Relative Modified Rankin Scale (mRS) [Срок оценки: 90 days, 180 days]
• Modified Rankin Scale (mRS) distribution [Срок оценки: 180 days]
• Glasgow Outcome Scale (GOS） [Срок оценки: 180 days]
• Questionnaire EuroQol Five Dimensions Questionnaire (EQ-5D) [Срок оценки: 180 days]
• Barthel Index for Activities of Daily Living (BI) [Срок оценки: 180 days]
• Total hospitalized time [Срок оценки: Discharge (assessed up to 30 days)]
• Total hospitalized costs [Срок оценки: Discharge (assessed up to 30 days)]
• Cerebral vasospasm (CV) [Срок оценки: 14 days]
• Delayed cerebral ischemia (DCI) [Срок оценки: 14 days]
• Death [Срок оценки: 180 days]
• Hydrocephalus [Срок оценки: 180 days]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Китай · 25 центров

• Anhui Provincial Hospital — Хэфэй
• The First Affiliated Hospital of Anhui Medical University — Heihe
• The First Affiliated Hospital of Fujian Medical University — Фучжоу
• Zhujiang Hospital of Southern Medical University — Гуанчжоу
• The First Affiliated Hospital of Harbin Medical University — Харбин
• Henan Provincial People's Hospital — Чжэнчжоу
• The First Affiliated Hospital of Zhengzhou University — Чжэнчжоу
• Renmin Hospital of Wuhan University — Ухань
• … и ещё 17 центров

Публикации

• Wu M, Yan T, Hu P, Wang C, Ye M, Yu Z, Wang Y, Mao G, Xiao B, Gong Y, Li J, Zhao R, Yang P, Liu J, Zhu X; LD-ITUK Investigators. Early lumbar drainage plus intrathecal urokinase in severe aneurysmal subarachnoid hemorrhage: the LD-ITUK randomized controlled trial protocol. Trials. 2026 Apr 13;27(1):379. doi: 10.1186/s13063-026-09716-1. PMID 41968344

Идентификаторы

NCT: NCT06284642 · LD-ITUK-2024-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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