Treatment of Acute Ischemic Stroke with Intravenous Urokinase (TASK-UK): Protocol for a Multicenter, Prospective, Real-World Study

Abstract

Background

Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) and urokinase (UK) are both recommended for acute ischemic stroke (AIS) in China. Compared with rt-PA, UK is less expensive and more widely available in clinical practice.

Objective

The Treatment of Acute Ischemic Stroke with Intravenous Urokinase (TASK-UK) study aims to investigate clinical outcomes among patients with AIS who receive UK thrombolysis, and to compare efficacy and cost-effectiveness between UK and rt-PA.

Methods

TASK-UK is a multicenter, real-world observational study, with a planned sample size of 1000 patients in the UK group and 800 in the rt-PA group. This study enrolls patients with AIS who are eligible for intravenous thrombolysis from 20 participating centers and conducts follow-up until 90 days after thrombolysis.

Planned Outcomes

The primary efficacy outcome is functional independence at 90 days, defined as a modified Rankin scale (mRS) score of 0–2. The primary safety outcome is symptomatic intracranial hemorrhage (sICH) occurring within 22–36 h after thrombolysis. The exploratory outcome is defined as an intergroup comparison of direct medical costs during hospitalization.

Discussion

The TASK-UK study will provide high-quality real-world evidence on the effectiveness and cost-effectiveness of UK thrombolysis for AIS.

Trial Registry Number

NCT06194968 (ClinicalTrials.gov).

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40120-026-01006-x.

Key Summary Points

Evidence comparing intravenous urokinase (UK) and recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke (AIS) remains insufficient, particularly regarding cost-effectiveness.

TASK-UK is a multicenter, prospective, real-world study evaluating UK versus rt-PA thrombolysis in patients with AIS across China.

A total of 1800 patients will be enrolled to assess functional outcomes, safety, and pharmacoeconomic outcomes after thrombolysis.

TASK-UK will provide real-world evidence to inform thrombolytic treatment selection and healthcare resource utilization for AIS.

Introduction

Background

Stroke remains one of the leading causes of morbidity and long-term disability worldwide [1, 2]. In China, approximately 3.4 million new stroke cases occur annually, of which 70–80% are acute ischemic stroke (AIS) [3]. For patients with hyperacute stroke, intravenous thrombolysis has been fully substantiated by high-quality evidence, demonstrating a significant reduction in the risk of death and disability, and an effective improvement in long-term functional prognosis [4, 5]. Current Chinese guidelines recommend intravenous thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) within 4.5 h or urokinase (UK) within 6 h after symptom onset [6].

In comparison with rt-PA, UK has several advantages, including lower cost, a longer time window, and wider availability in clinical practice [7]. It is noteworthy that the thrombolysis cost of UK is approximately 1200 Chinese yuan (CNY), which is substantially lower—about one-fifth—than that of rt-PA (approximately CNY 5500). Evidence from the large-scale randomized TRUST trial indicates that UK intravenous thrombolysis is relatively safe in patients with acute minor stroke [8]. However, the existing evidence comparing the effectiveness of UK and rt-PA remains limited and inconclusive. A prospective multicenter registry study suggested that UK has efficacy comparable to rt-PA in mild-to-moderate AIS without increasing the risk of symptomatic intracranial hemorrhage (sICH) [9]. Similarly, analysis of data from the China Stroke Center Alliance (CSCA) registry demonstrated that UK thrombolysis was associated with lower risks of hemorrhage transformation and in-hospital mortality compared to rt-PA [10]. In contrast, another multicenter study reported similar outcomes but a higher risk of extracranial bleeding with UK [11].

Objective

To our knowledge, no studies have directly compared the cost-effectiveness of UK and rt-PA. Moreover, the optimal dosing strategy and the patient populations most likely to benefit from UK require further investigation. The Treatment of Acute Ischemic Stroke with Intravenous Urokinase (TASK-UK) study aims to investigate the effectiveness and cost-effectiveness of intravenous thrombolysis with UK compared with rt-PA in patients with AIS in real-world settings, thereby providing critical evidence to inform clinical practice and healthcare decision-making.

Methods

Study Design

The TASK-UK study (ClinicalTrials.gov ID NCT06194968) is a multicenter, real-world observational study. A total of 1000 patients with AIS receiving intravenous UK thrombolysis are prospectively enrolled from 20 clinical centers nationwide as the observational group, while 800 patients treated with intravenous rt-PA thrombolysis are retrospectively included during the same period as the control group. Patients in both groups are recruited from the same participating centers during the same study period. The participating centers and study investigators are listed in Table S1. Patients who receive UK within 4.5 h will be compared with those who receive rt-PA within the same time window to optimize the treatment protocol and economic effects of AIS. The study patient flow outline is shown in Fig. 1. The TASK-UK study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Approval No. 2023-KY-0983-002) and all participating centers. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all participants in the UK group, whereas the requirement for written informed consent was waived for the rt-PA group by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University because only de-identified electronic medical record data are used.

Fig. 1.

Flowchart. AIS acute ischemic stroke, UK urokinase, rt-PA recombinant tissue plasminogen activator, HEMR hospital electronic medical records, mRS modified Rankin scale, NIHSS National Institutes of Health Stroke Scale, sICH symptomatic intracranial hemorrhage, AEs adverse events, SAEs serious adverse events

Dissemination

The findings of the TASK-UK study will be disseminated through publications in a peer-reviewed scientific journal and presentations at relevant national and international scientific conferences. The results will be shared with key clinical stakeholders, including neurologists and primary care physicians, to inform clinical decision-making and optimize thrombolytic treatment strategies for patients with AIS.

Sample Selection

Inclusion criteria include (1) age ≥ 18 years; (2) clinical diagnosis of AIS; (3) first onset of stroke or a previous history of stroke without significant neurological disability, defined as a modified Rankin scale (mRS) score ≤ 1; (4) eligibility for intravenous thrombolysis with UK or rt-PA as assessed by the investigators; (5) informed consent from patients or their guardians. Key exclusion criteria include (1) contraindications for intravenous thrombolysis; (2) pregnant or lactating women; (3) drug abuse or dependence within the previous year; (4) other situations that researchers believe are not suitable for participating in the study. The full inclusion and exclusion criteria are summarized in Table S2. Contraindications for intravenous thrombolysis are summarized in Table S3.

Treatments

In accordance with the recommended dosing regimens of the Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke (2018), patients receive intravenous thrombolysis with UK (1.0–1.5 million IU) or rt-PA (0.9 mg/kg over 60 min). All other management, including the selection of bridging therapy and the use of antiplatelets, statins, and antihypertensive medications, are determined by the clinicians on the basis of the patient’s age, imaging findings, and neurological severity.

Measurements

We will comprehensively assess and compare the clinical effectiveness, safety, and exploratory economic outcomes between patients with AIS treated with UK and those treated with rt-PA in real-world settings. All functional neurological outcomes, bleeding events, adverse events (AEs), and economic outcomes will be evaluated according to standardized stroke assessment scales, internationally accepted diagnostic criteria, and imaging-confirmed assessments. Predefined time windows will be strictly applied for all outcome assessments to ensure uniformity and consistency in outcome evaluation across participating centers.

Planned Outcomes

Primary Efficacy Outcome

The primary efficacy outcome is the proportion of patients achieving functional independence (defined as a mRS score of 0–2) at 90 days.

Secondary Efficacy Outcomes

1. Distribution of mRS score at 90 days after treatment

2. Changes of the National Institutes of Health Stroke Scale (NIHSS) at 22–36 h after thrombolysis compared with the baseline

3. Changes of NIHSS at 7 days after the treatment from the baseline

Primary Safety Outcome

The primary safety outcome is the incidence of symptomatic intracranial hemorrhage (sICH) as defined by the European Cooperative Acute Stroke Study III (ECASS-III) criteria [12] within 22–36 h following thrombolysis.

Secondary Safety Outcomes

1. Incidence of all bleeding events during hospitalization, with severity stratified using the PLATelet inhibition and patient Outcomes (PLATO) [13] bleeding classification.

2. Incidence of intracranial hemorrhage events during hospitalization, with all events objectively confirmed by cranial computed tomography (CT) or magnetic resonance imaging (MRI).

3. Incidence of AEs and serious adverse events (SAEs). The severity of TEAEs was graded in accordance with the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0).

Exploratory Outcome

Pharmacoeconomic evaluation: between-group comparison of inpatient direct medical costs to preliminarily explore potential differences in hospitalization expenses between treatment groups.

Data Collection

Patients in the UK group are enrolled prospectively and consecutively. Clinical data for patients in the UK group will be collected at each center using an electronic data capture system (EDC) or a paper-based case report form (CRF). The schedule of study assessments is presented in Table 1. Demographic characteristics, vital signs, laboratory results, medication usage, concomitant therapies, and AEs of patients will be collected at baseline, during thrombolysis, at 7 days, and at 90 days after thrombolysis. For the retrospective rt-PA group, clinical data, and AEs will be systematically collected through comprehensive review of EMRs, including inpatient records and archived follow-up data. All AEs will also be comprehensively collected and documented according to standardized assessment criteria.

Table 1.

Schedule of study assessments

Study procedure	Screening	Treatment	Follow-up
	Enrollment/baseline	Thrombolytic period	Hospitalization period or 7 ± 2 days after thrombolysis	90 ± 10 days after thrombolysis (telephone)
Enrollment
Eligibility screen	X
Informed consent form (UK group)	X
Demographic data	X
Medical history	X
Vital signs	X	Xa	X
Physical examination	X
Blood routine	X		X (if applicable)
Blood biochemistry	X		X (if applicable)
Coagulation function	X		X (if applicable)
Brain CT/MRI	X		X (if applicable)
Electrocardiograph	X
TOAST classification			X
Assessments
mRS	X		Xc	X
NIHSS	X	Xb	Xc
EQ-5D-5L			Xc	X
Survival				X
Adverse events	X	X	X	X
Treatment record
Usage of urokinase		X
Companion therapy		X	X	X
Hospital course			X
Related expenses for the treatment of this disease			X
Concomitant medication	X	X	X	X

CT computed tomography scan, MRI magnetic resonance imaging, TOAST Trial of Org 10172 in Acute Stroke Treatment, mRS modified Rankin scale, NIHSS National Institutes of Health Stroke Scale, GCS, EQ-5D-5L five-level EuroQol five-dimensional questionnaire

^aImmediately after thrombolysis

^b22–36 h after thrombolysis

^cPrior to discharge

Data Quality Assurance and Control

Several approaches are implemented to minimize the potential data heterogeneity and ensure data accuracy. Specifically, to minimize information bias arising from the two data collection methods, a standardized data extraction template and AEs verification checklist were established to ensure that all baseline, efficacy, and safety outcomes were adjudicated using fully uniform criteria. The investigators from all centers receive standardized training before patient enrollment to ensure familiarity with the study protocol and the use of unified data recording procedures and evaluation criteria. An independent monitoring team is responsible for reviewing the eCRF to ensure data completeness and quality. All intracranial hemorrhage-related outcomes were subjected to secondary verification against cranial CT/MRI imaging data to maximize the homogeneity and comparability of data between the two groups. In addition, throughout the entire process of clinical trials, clinical trial participants, investigators, and monitors strictly follow the requirements of the Clinical Trial Quality Management Practice (GCP) to ensure standardized trial procedures, accurate data, and reliable research conclusions.

Sample Size Estimates

This observational cohort study includes two treatment groups. The sample size calculation assumes that, among patients with AIS treated within 4.5 h of symptom onset, intravenous thrombolysis with UK is non-inferior to rt-PA in terms of functional outcome. The sample size is estimated on the basis of the proportion of patients with mRS score of 0–2 at 90 days. Previous studies have shown that, among patients with AIS treated within 4.5 h of symptom onset, the proportion of mRS score 0–2 at 90 days for UK and rt-PA was 79.5% and 81.5%, respectively [9]. Assuming a one-sided α of 0.025, a statistical power of 0.8, a non-inferiority margin of 8%, and a 1:1 allocation ratio between the UK and rt-PA groups and a 5% loss to follow-up, we estimated the required sample size to be 720 patients per group. On the basis of previous AIS thrombolysis studies [14, 15], a non-inferiority margin of 5–10% is commonly used for the proportion of patients achieving a mRS score 0–2 at 90 days. An 8% non-inferiority margin is adopted in this study to ensure clinical relevance while balancing enrollment feasibility and study robustness. Considering the potential influence of confounding variables in real-world settings, the sample size was expanded by approximately 10% and increased to 800 patients per group. Furthermore, clinical estimates indicate that approximately 80% of patients with AIS receiving UK thrombolysis within 6 h symptom onset are treated within the first 4.5 h. Accordingly, this study plans to enroll 1000 patients treated with UK within 6 h and 800 patients treated with rt-PA within 4.5 h, resulting in a total planned sample size of 1800 patients.

Data Analysis

In descriptive analyses, continuous variables will be summarized as mean ± standard deviation (SD), median with interquartile range (IQR), or range (maximum, minimum). Categorical data will be presented as frequencies and percentages based on non-missing data. Baseline clinical characteristics will be compared between the UK group and rt-PA group using two-sample t tests or the Mann–Whitney test as appropriate for continuous variables and Fisher’s exact test or χ² test for categorical variables.

Intergroup comparisons and non-inferiority analyses of efficacy and safety outcomes will be restricted to patients in the UK and rt-PA groups treated within 0–4.5 h of symptom onset, representing the shared therapeutic window for both treatments. Patients in the UK group treated within 4.5–6 h after symptom onset will be included in descriptive analyses only. For intergroup comparisons of primary outcome, multivariable binary logistic regression will be used to adjusted potential confounding covariates, and odds ratio with its 95% confidence interval (CI) will be reported. Multivariable ordinal logistic regression will be used for the distribution of mRS score at 90 days. General linear models or Mann–Whitney test will be used for the secondary outcomes of changes of NIHSS and medical costs. Furthermore, inverse probability weighting will be conducted to adjust for baseline confounders, including age and disease severity, with propensity score matching as a sensitivity analysis. Prespecified subgroup analyses in the weighted cohort will be performed using the proportion of patients achieving a mRS score of 0–2 at 90 days as the efficacy outcome, with stratification by age, sex, baseline NIHSS score, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and receipt of endovascular thrombectomy. In addition, restricted cubic spline modeling will be applied, with weight-adjusted UK dose (× 10⁴ U/kg) entered as an independent variable, to characterize potential dose–response associations with the primary efficacy and safety outcomes. All statistical analyses will be performed using SAS software (version 9.4; SAS Institute, Cary, NC, USA). All tests will be two-sided, with P < 0.05 considered statistically significant.

Discussion

The TASK-UK study is a prospective, observational study conducted in routine clinical practice across China, aiming to evaluate the effectiveness and cost-effectiveness of UK and rt-PA in patients with AIS. This study represents the first real-world investigation to concurrently evaluate the effectiveness and cost-effectiveness of UK versus rt-PA therapy for AIS. The primary objective is to explore whether UK intravenous thrombolysis can ensure effectiveness while reducing the healthcare costs in real-world settings. The findings of this study may provide evidence to support clinical decision-making and optimize healthcare resource allocation in the management of AIS.

The research conducted by the Chinese government during the “Ninth Five-Year Plan” period showed that patients with AIS who received UK within 6 h exhibited significant improvements in NIHSS scores and clinical symptoms [16, 17]. However, with the continuous development of medical research and therapeutic technologies, these findings require validation in real-world clinical settings. The present study was designed as a prospective observational real-world study with relatively broad eligibility criteria to obtain a representative patient population and generate findings applicable to routine clinical practice. Although randomized controlled trials (RCTs) are considered the gold standard for determining treatment efficacy, their strict inclusion and exclusion criteria may limit the generalizability of their findings to real-world populations [18, 19]. In contrast, the current study includes a large and more heterogeneous patient population, including elderly individuals and patients with comorbidities who are frequently underrepresented in RCTs. Therefore, although the level of evidence provided by this study is lower than that of RCTs, its findings may have greater external validity and clinical applicability. However, the non-randomized design of this study may introduce confounding and selection bias, which presents challenges for causal inference. Nevertheless, we adopted a concurrent control design in which the comparison group was recruited during the same time period and from the same clinical settings as the observation group. This approach reduces potential bias related to temporal differences and enhances comparability between groups [20]. A similar strategy has been applied in previous studies evaluating the cost-effectiveness of stroke care, including the study by van Exel and colleagues [21].

Strengths and Limitations

A further strength of this study is that the UK used was uniformly sourced from a single manufacturer, which reduces potential variability and minimizes a possible source of bias compared with previous studies, such as that reported by Wang et al. [9]. Moreover, our study was conducted across 20 hospitals at different levels, located in 10 major regions of China, including central, northern, northwestern, northeastern, and southern areas (Table S1). This design captures a patient population with considerable geographic, economic, and cultural diversity, thereby enhancing the representativeness of its conclusions for the broader Chinese demographic. These participating centers include top tertiary hospitals and regional medical centers, which reflect real-world clinical practice in China. It is worth noting that this study was prospectively registered with ClinicalTrials.gov, ensuring full transparency of the study protocol and safeguarding the integrity of the findings.

The outcomes of this study are consistent with those commonly used in RCTs of thrombolysis for AIS, including the mRS score, NIHSS score, and incidence of hemorrhage events [4, 22]. Furthermore, to address the practical challenges of healthcare delivery, we incorporated a pharmacoeconomic evaluation as an exploratory outcome. The results of this cost-effectiveness analysis are intended to provide actionable evidence for informed decision-making regarding the optimal allocation of medical resources.

Although the TASK-UK study is expected to provide valuable insights into thrombolytic therapy for AIS, we must nevertheless acknowledge its limitations. First, although all participants were drawn from the same centers and the same enrollment period with standardized data collection forms, the differential data collection methods and observational design may introduce potential biases and confounding. To reduce the bias, statistical strategies that control for confounding factors will be implemented, including multivariate regression analysis and propensity score matching. Second, although this is a multicenter study, the participating centers were not randomly selected, which may introduce selection bias. However, the inclusion of centers representing different healthcare settings may also enhance the relevance of the findings to routine clinical practice. Third, the study enrolls only Chinese patients, whose body weight distribution, comorbidity profile, and cerebrovascular-disease subtypes differ from those of the broader AIS population, potentially limiting the generalizability of the findings. Finally, tenecteplase was not included as a comparator, as it had not yet been incorporated into the national medical insurance reimbursement and remained of limited clinical availability in most hospitals during the early stage of study design. As evidence accumulates and its clinical adoption expands, future studies are warranted to compare the efficacy and safety of different thrombolytic agents to inform individualized thrombolysis.

Conclusion

The TASK-UK study is expected to provide real-world evidence regarding the clinical effectiveness and economic value of UK for patients with AIS, and its findings may serve as pivotal evidence for optimizing clinical pathways and resource allocation.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Yongli Tao: Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing—original draft. Hui Fang: Data curation, Formal analysis, Supervision, Writing—original draft. Lulu Pei: Formal analysis, Methodology, Visualization. Yuan Gao: Data curation, Formal analysis, Supervision, Writing—original draft. Kai Liu: Data curation, Investigation, Validation. Xin Wang: Resources, Validation. Rui Zhang: Data curation, Formal analysis, Supervision, Writing—original draft. Zhentang Cao: Formal analysis, Methodology, Visualization. Yifang Zhou: Data curation, Investigation, Resources. Ding Zhang: Data curation, Investigation, Resources. Yiwei Qian: Data curation, Investigation, Resources. Yuesong Pan: Data curation, Investigation, Resources. Yuming Xu: Data curation, Investigation, Resources. Bo Song: Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Writing—review and editing.

Funding

This study was funded by Techpool Bio-Pharma Co., Ltd. No input from the funder was received regarding trial design, data acquisition and analysis, result interpretation, or manuscript preparation; accordingly, the funder had no bearing on the study outcomes. The funder also covered the journal’s Rapid Service Fee.

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Yongli Tao, Hui Fang, Lulu Pei, Yuan Gao, Kai Liu, Xin Wang, Rui Zhang, Zhentang Cao, Yifang Zhou, Ding Zhang, Yiwei Qian, Yuesong Pan, Yuming Xu, Bo Song declare that they have no conflicts of interest.

Ethical Approval

The TASK-UK study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (Approval No. 2023-KY-0983-002) and all participating centers. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Written informed consent was obtained from all participants in the UK group, whereas the requirement for written informed consent was waived for the rt-PA group by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University because only de-identified electronic medical record data are used.