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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Urokinase; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Estimated): 424
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Xingen Zhu, MS; Phone Number: 13803546020; Email: zxg2008vip@163.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230000
      • Recruiting
      • Anhui Provincial Hospital
      • Contact: Yang Wang, MD
    • Heihe, Anhui, China, 230000
      • Recruiting
      • The First Affiliated Hospital of Anhui Medical University
      • Contact: Lei Ye, MD
  • Fujian
    • Fuzhou, Fujian, China, 350000
      • Recruiting
      • The First Affiliated Hospital of Fujian Medical University
      • Contact: Dengliang Wang, MD
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Recruiting
      • ZhuJiang Hospital of Southern Medical University
      • Contact: Xin Feng, MD
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150000
      • Recruiting
      • The First Affiliated Hospital of Harbin Medical University
      • Contact: Jingtao Qi, MD
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Recruiting
      • The First Affiliated Hospital of Zhengzhou University
      • Contact: Zhiqiang Yao, MD
    • Zhengzhou, Henan, China, 450000
      • Recruiting
      • Henan Provincial People's Hospital
      • Contact: Guang Feng, MD
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Hua li, MD
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Renmin Hospital of Wuhan University
      • Contact: Mingchang Li, MD
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Zhongnan Hospital of Wuhan University
      • Contact: Wei Wang, MD
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Union hospital,Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Yin Shen, MD
  • Hunan
    • Changsha, Hunan, China, 410000
      • Recruiting
      • Xiangya Hospital of Central South University
      • Contact: Yuchun Zuo, MD
  • Jiangsu
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • the First Affiliated Hospital of Nanjing Medical University
      • Contact: Yifei Wang, MD
    • Nanjing, Jiangsu, China, 210000
      • Recruiting
      • Nanjing Drum Tower Hospital
      • Contact: Penglai Zhao, MD
    • Wuxi, Jiangsu, China, 214000
      • Recruiting
      • 904th Hospital of Joint Logistic Support Force of PLA
      • Contact: Junhui Chen, MD
  • Jiangxi
    • Ganzhou, Jiangxi, China, 341000
      • Recruiting
      • First Affiliated Hospital of Gannan Medical University
      • Contact: Zhaobin Zhao, MD
    • Ganzhou, Jiangxi, China, 341000
      • Recruiting
      • Ganzhou People's Hospital
      • Contact: Zhenyu Zhang, MD
    • Nanchang, Jiangxi, China, 330006
      • Recruiting
      • The Second Affiliated Hospital of Nanchang University
      • Contact: Xingen Zhu, MS; Email: zxg2008vip@163.com
  • Shandong
    • Jinan, Shandong, China, 250000
      • Recruiting
      • Qilu Hospital of Shandong University
      • Contact: Ping Zhang, MD
    • Jinan, Shandong, China, 250000
      • Recruiting
      • The First Affiliated Hospital of Shandong First Medical University
      • Contact: Chuanjiang Huang, MD
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200000
      • Recruiting
      • Changhai Hospital, Naval Medical University
      • Contact: Rui Zhao, MD
    • Shanghai, Shanghai Municipality, China, 200000
      • Recruiting
      • Huashan Hospital of Fudan University
      • Contact: Dengliang Wang, MD
  • Sichuan
    • Chengdu, Sichuan, China, 610000
      • Recruiting
      • Sichuan Provincial People's Hospital
      • Contact: Chunling Li, MD
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • The Second Affiliated Hospital of Zhejiang University School of Medicine
      • Contact: Xiaoyu Wang, MD
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • First Affiliated Hospital, Zhejiang University School of Medicine
      • Contact: Kaiyuan Huang, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: lumbar drainage combined with intrathecal urokinase injection	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.; Other Names: Urokinase-type plasminogen activator
Placebo Comparator: lumbar drainage; lumbar drainage combined with intrathecal placebo saline injection	Drug: 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.; Other Names: Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS)	Good (mRS 0-2) and Poor (mRS 3-6)	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin Scale (mRS) distribution	On the distributed proportion in scores (0-6) on the mRS	180 days
Death	Occurence of any death during follow-up after operation	180 days
Hydrocephalus	Occurence of a hydrocephalus after-onset	180 days
Rebleeding	Occurence of a rebleeding after-onset	30 days
Modified Rankin Scale (mRS)	Good (mRS 0-2) and Poor (mRS 3-6)	90 days
Relative Modified Rankin Scale (mRS)	Good (mRS 0-3) and Poor (mRS 4-6)	90 days, 180 days
Glasgow Outcome Scale (GOS）	Good (GOS 4-5) and Poor (GOS 1-3)	180 days
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
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
Total hospitalized time	Toal hospitalized time from ofter-onset to discharge, including neurocritical care unit	Discharge (assessed up to 30 days)
Total hospitalized costs	Toal hospitalized costs from ofter-onset to discharge	Discharge (assessed up to 30 days)
Cerebral vasospasm (CV)	Occurence of any symptomatic or image CV after aSAH	14 days
Delayed cerebral ischemia (DCI)	Occurence of any symptomatic or image DCI after aSAH	14 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subarachnoid hemorrhage volume clearance	dynamic clearance of subarachnoid hemorrhage volume on non-contrast CT scans ofter-onset to discharge	30 days
Correlationship between cerebralspinal fluid pressure with subarachnoid hemorrhage volume	correlationship between admission cerebralspinal fluid pressure with subarachnoid hemorrhage volume	72 hours after-onset
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

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital of Nanchang University
• Collaborators: The First Affiliated Hospital with Nanjing Medical University; The First Affiliated Hospital of Anhui Medical University; Xiangya Hospital of Central South University; Huashan Hospital; Tongji Hospital; Qilu Hospital of Shandong University; First Affiliated Hospital of Fujian Medical University; Xuanwu Hospital, Beijing; The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School; The First Affiliated Hospital of Zhengzhou University; Zhongnan Hospital; Henan Provincial People's Hospital; Qianfoshan Hospital; Renmin Hospital of Wuhan University; Zhejiang University; The Second Affiliated Hospital of Harbin Medical University; Southern Medical University, China; Sichuan Provincial People's Hospital; Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University; First Affiliated Hospital of Harbin Medical University; Yichang Central People's Hospital; Liaocheng People's Hospital; Linyi People's Hospital; First Affiliated Hospital of Gannan Medical University; Panzhihua Central Hospital; Jiujiang No.1 People's Hospital; The Second Military Medical University Changhai Hospital; Xianning Central Hospital; The First People's Hospital of Changde City; Ganzhou City People's Hospital; Dezhou Hospital Qilu Hospital of Shandong University; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; 904th Hospital of the Joint Logistics Support Force of the PLA
• Investigators: Principal Investigator: Xingen Zhu, MS, Second Affiliated Hospital of Nanchang University

Publications and helpful links

General Publications

• 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. doi: 10.1186/s13063-026-09716-1. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2024
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: February 1, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 29, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Hemorrhage; Intracranial Hemorrhages; Pathological Conditions, Signs and Symptoms; Subarachnoid Hemorrhage; Amino Acids, Peptides, and Proteins; Proteins; Hydrolases; Enzymes; Enzymes and Coenzymes; Blood Proteins; Inorganic Chemicals; Chlorine Compounds; Endopeptidases; Peptide Hydrolases; Sodium Compounds; Serine Endopeptidases; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Chlorides; Hydrochloric Acid; Sodium Chloride; Urokinase-Type Plasminogen Activator
• Other Study ID Numbers: LD-ITUK-2024-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No