Thrombolysis with Recombinant Human Prourokinase 4.5–6 h After Acute Ischemic Stroke: A Phase IIa, Randomized, and Open-Label Multicenter Clinical Trial,CNS Drugs

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Thrombolysis with Recombinant Human Prourokinase 4.5–6 h After Acute Ischemic Stroke: A Phase IIa, Randomized, and Open-Label Multicenter Clinical Trial
CNS Drugs ( IF 6 ) Pub Date : 2023-11-29 , DOI: 10.1007/s40263-023-01051-2
Haiqing Song ₁ , Yuan Wang ₁ , Qingfeng Ma ₁ , Huisheng Chen ₂ , Bo Liu ₃ , Yi Yang ₄ , Jianguo Zhu ₅ , Shigang Zhao ₆ , Xiaoping Jin ₇ , Yongqiu Li ₈ , Yanyong Wang ₉ , Runxiu Zhu ₁₀ , Liandong Zhao ₁₁ , Junyan Liu ₁₂ , Wuwei Feng ₁₃ , Rui Liu ₁₄ , Xunming Ji ₁₅ , Yuping Wang ₁

Affiliation

Department of Neurology, Xuanwu Hospital, Capital Medicine University, 45 Chang Chun St, Beijing, 100053, China.
Department of Neurology, The General Hospital of Shenyang Military, Shenyang, Liaoning, China.
Department of Neurology, The First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China.
Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Neurology, Halison International Peace Hospital, Hengshui, Hebei, China.
Department of Neurology, The Affiliated Hospital of Inner Mogolia Medical University, Huhhot, Inner Mogolia, China.
Department of Neurology, TaiZhou Hospital of Zhejiang Province, Taizhou, Zhejiang, China.
Department of Neurology, Tangshan Worker's Hospital, Tangshan, Hebei, China.
Department of Neurology, The First Hospital of Hebei University, Shijiazhuang, Hebei, China.
Department of Neurology, Inner Mongolia People's Hospital, Huhhot, Inner Mogolia, China.
Department of Neurology, The Second People's Hospital of Huai'an, Huai'an, Jiangsu, China.
Department of Neurology, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
Department of Clinical Medicine, Tasly Biopharmaceuticals Co., Ltd, Tianjin, China.
Department of Neurosurgery, Xuanwu Hospital, Capital Medicine University, 45 Chang Chun St, Beijing, 100053, China.

Background

Ischemic stroke is a major cause of disability and death worldwide. A narrow therapeutic window profoundly constrained the utilization of alteplase.

Objectives

To investigate therapeutic effects and safety of intravenous recombinant human prourokinase (rhPro-UK) in patients with acute ischemic stroke (AIS) in the 4.5–6 h therapeutic time windows.

Methods

We conducted a phase IIa, randomized, and open-label multicenter clinical trial. Between 4.5 and 6 h after the onset of AIS, patients were randomly administrated to receive intravenous rhPro-UK at a 50 mg or 35 mg dose. The primary endpoint was excellent functional outcome defined as modified Rankin scale (mRS) score of 1 or less at 90 days. The secondary outcome was the treatment response, which was based on an at least 4-point improvement from baseline National Institutes of Health stroke scale (NIHSS) score at 24 h after drug administration. Safety endpoints included death, symptomatic intracerebral hemorrhage (sICH), and other serious adverse events.

Results

We enrolled 80 patients in the 4.5–6 h therapeutic time windows at 17 medical centers in China from December 2016 to November 2017. A total of 39 patients were treated with 50 mg rhPro-UK, and 39 were treated with 35 mg rhPro-UK. Compared with the baseline, the NIHSS score at 24 h and days 7, 14, 30, and 90 was decreased significantly among patients treated with either rhPro-UK 50 mg or 35 mg. The mean reduction in the NIHSS from baseline to 90 days after the onset was 3.56 and 5.79 in the rhPro-UK 50 mg group and the rhPro-UK 35 mg group, respectively. The rates of functional independence at 90 days of rhPro-UK 50 mg and 35 mg were 61.54% and 69.23%, respectively (P = 0.475), and the proportion of patients with functional response to treatment at 24 h were 28.21% and 33.33% (P = 0.624). No sICH occurred in the two groups, and death occurred in only one patient in the rhPro-UK 50 mg group. There was no significant difference in mortality at 90 days and the rate of other serious adverse events between two groups.

Conclusion

In the 4.5–6 h time window, more than 60% of patients at either dose of rhPro-UK (50 mg or 35 mg) achieved functional independence at 90 days without increased mortality and sICH risk. Thus, intravenous rhPro-UK was effective and safe for patients with AIS within 4.5–6 h after stroke onset. While no significant differences were identified between different dosages of rhPro-UK regarding clinical outcomes, it is a logical step to further test the safety and efficacy of the low dose of rhPro-UK in a well-powered phase III study.