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Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Phase IIa Randomized Clinical Trial

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Abstract

Recombinant human prourokinase (rhPro-UK) is a novel thrombolytic that has been approved to treat patients with acute myocardial infarction. However, the safety and efficacy of intravenous rhPro-UK in patients with acute ischemic stroke (AIS) has not been well established. We aimed to investigate the safety and preliminary efficacy of rhPro-UK in patients with AIS in a multi-center phase IIa trial setting. One hundred nineteen patients within 4.5 h of AIS onset were enrolled in this randomized, open-label, 23-center phase IIa clinical trial. Patients were randomly assigned to 35 mg (n = 40) or 50 mg (n = 39) intravenous rhPro-UK or 0.9 mg/kg recombinant tissue plasminogen activator (r-tPA; n = 40). The primary endpoint was functional independence defined as a modified Rankin scale (mRS) score of 0 or 1 at 90 days. The secondary outcome was early neurological improvement defined as a reduction of ≥ 4 points on the National Institutes of Health Stroke Scale (NIHSS) score from baseline to 24 h after drug administration. Safety endpoints included death due to any cause, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events (SAEs). The proportion of patients with an mRS score of ≤ 1 at 90 days did not differ significantly among three groups (35 mg rhPro-UK: 55.56% vs. 50 mg rhPro-UK: 57.89% vs. vs. r-tPA: 52.63%; P = 0.92). The rates of treatment response, referring to early neurological improvement, were similar among these three groups (36.11% vs. 31.58% vs. 28.95%, respectively; P = 0.85). There was no difference in mortality at 90 days or in the rate of other SAEs among the three groups. One patient in the 50 mg rhPro-UK group suffered sICH. While neither the primary efficacy outcomes nor safety profile differed significantly among the low, high rhPro-UK and control groups, it is a logical step to further test the low-dose rhPro-UK group versus the control group in a well-powered phase III study.

Trial Registration: http://www.chictr.org.cn. Identifier: ChiCTR1800016519. Date of registration: June 6 2018.

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Data Availability

Data are available to researchers on request for purpose of reproducing the results or replicating the procedure by directly contacting the corresponding author.

Abbreviations

AIS:

Acute ischemic stroke

CT:

Computed tomography

ICH:

Intracranial hemorrhage

mRS:

Modified Rankin Scale

NIHSS:

National Institutes of Health Stroke Scale

Pro-UK:

Pro-urokinase

rhPro-UK:

Recombinant human prourokinase

r-tPA:

Recombinant tissue plasminogen activator

SAEs:

Serious adverse events

sICH:

Symptomatic intracerebral hemorrhage

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Acknowledgements

We would like to thank all patients who participated in this study. We also thank all the research team and clinical staff for their efforts and time.

Funding

This trial was funded by a grant from the Tasly Biopharmaceuticals Co., Ltd.

Author information

Authors and Affiliations

  1. Department of Neurology, Xuanwu Hospital, Capital Medicine University, 45 Chang Chun St, Beijing, 100053, China

    Haiqing Song, Yuan Wang, Qingfeng Ma & Yuping Wang

  2. Department of Neurology, The General Hospital of Shenyang Military, Shenyang, Liaoning, China

    Huisheng Chen

  3. Department of Neurology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China

    Bo Liu

  4. Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China

    Yi Yang

  5. Department of Neurology, Halison International Peace Hospital, Hengshui, Hebei, China

    Jianguo Zhu

  6. Department of Neurology, The Affiliated Hospital of Inner Mogolia Medical University, Huhhot, Inner Mogolia, China

    Shigang Zhao

  7. Department of Neurology, TaiZhou Hospital of Zhejiang Province, Taizhou, Zhejiang, China

    Xiaoping Jin

  8. Department of Neurology, Tangshan Worker’s Hospital, Tangshan, Hebei, China

    Yongqiu Li

  9. Department of Neurology, The First Hospital of Hebei University, Shijiazhuang, Hebei, China

    Yanyong Wang

  10. Department of Neurology, Inner Mongolia People’s Hospital, Huhhot, Inner Mogolia, China

    Runxiu Zhu

  11. Department of Neurology, The Second People’s Hospital of Huai’an, Huai’an, Jiangsu, China

    Liandong Zhao

  12. Department of Neurology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Junyan Liu

  13. Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China

    Qilin Ma

  14. Department of Neurology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China

    Yongzhong Lin

  15. Department of Neurology, Huai’an First People’s Hospital, Huai’an, Jiangsu, China

    Xiangyang Tian

  16. Department of Neurology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China

    Qing Zhang

  17. Department of Neurology, China Meitan General Hospital, Beijing, China

    Weidong Zhou

  18. Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Yongbo Zhang

  19. Department of Neurology, Chongqing Sanxia Center Hospital, Chongqing, China

    Jie Zhou

  20. Department of Neurology, Shenyang 463 Hospital, Shenyang, Liaoning, China

    Yansong Li

  21. Department of Neurology, The Third Xiangya Hospital of General South University, Changsha, Hunan, China

    Zhi Song

  22. Department of Neurology, Duke University School of Medicine, Durham, NC, USA

    Wuwei Feng

  23. Department of Clinical Medicine, Tasly Biopharmaceuticals Co., Ltd, Tianjin, China

    Rui Liu

  24. Department of Neurosurgery, Xuanwu Hospital, Capital Medicine University, 45 Chang Chun St, Beijing, 100053, China

    Xunming Ji

Authors
  1. Haiqing Song
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  2. Yuan Wang
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  3. Qingfeng Ma
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  4. Huisheng Chen
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  5. Bo Liu
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  6. Yi Yang
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  7. Jianguo Zhu
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  8. Shigang Zhao
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  9. Xiaoping Jin
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  10. Yongqiu Li
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  11. Yanyong Wang
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  12. Runxiu Zhu
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  13. Liandong Zhao
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  14. Junyan Liu
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  15. Qilin Ma
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  16. Yongzhong Lin
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  17. Xiangyang Tian
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  18. Qing Zhang
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  19. Weidong Zhou
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  20. Yongbo Zhang
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  21. Jie Zhou
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  22. Yansong Li
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  23. Zhi Song
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  24. Wuwei Feng
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  25. Rui Liu
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  26. Xunming Ji
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  27. Yuping Wang
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Contributions

Drs Song HQ and Wang Y contributed equally as co-first authors. Drs Wang YP and Ji XM had full access to all the data in the study and were responsible for the integrity of the data and the accuracy of the data analysis. Drs Song HQ, Ma QF, Chen HS, Liu B, Yang Y, Ji XM and Wang YP contributed to the study concept and design. All authors acquired, analyzed and interpreted the data. Drs Song HQ and Wang Y wrote the first draft the manuscript. Drs Feng W, Ji XM and Wang YP provided critical revision of the manuscript for important intellectual content. All authors provided administrative, technical or material support, and approved the final manuscript.

Corresponding authors

Correspondence to Xunming Ji or Yuping Wang.

Ethics declarations

Ethic approval

The clinical trial was accepted by the National Medical Products Administration (No. 2016L05323) and approved by the institutional review boards of the 23 participating centers. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Informed consent

Written informed consent was obtained from all patients prior to enrollment.

Conflicts of interest

Dr Liu R reports being an employee of Tasly Biopharmaceuticals Co.,Ltd,. No other potential conflict of interest relevant to this article was reported.

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Dr HQ Song and Dr Y Wang contributed equally to this work and should share the first authorship

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Song, H., Wang, Y., Ma, Q. et al. Efficacy and Safety of Recombinant Human Prourokinase in Acute Ischemic Stroke: A Phase IIa Randomized Clinical Trial. Transl. Stroke Res. 13, 995–1004 (2022). https://doi.org/10.1007/s12975-022-01012-9

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  • DOI: https://doi.org/10.1007/s12975-022-01012-9

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