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Efficacy and Safety of Recombinant Human Prourokinase in the Treatment of Acute Ischemic Stroke within 4·5 Hours of Stroke Onset (PROST): A Phase 3, Randomised, Open-Label, Non-Inferiority Trial
Posted: 6 Jun 2022
More...Abstract
Background: Recombinant human prourokinase (rhPro-UK) is a thrombolytic agent that has shown promising data in a phase 2 clinical trial in acute ischemic stroke (AIS).
Methods: In this prospective randomised phase 3 trial, 663 patients were randomly assigned (1:1) to receive intravenous rhPro-UK (n = 330) or alteplase (n = 333) within 4·5 hours of AIS onset. The primary objective was to assess whether rhPro-UK was noninferior to alteplase. Noninferiority margin was defined as a between-group difference of less than 10 percentage points. The primary outcome was a modified Rankin Scale score of 0-1 at 90 days. This study was registered at ClinicalTrials.gov, number NCT03541668.
Findings: Of 684 patients screened from May 2018 to May 2020, 663 were enrolled for the trial. Patients were randomly assigned 1:1 to each thrombolytic therapy arm. The median baseline National Institutes of Health Stroke Scale score was 6·00 (interquartile range, 5·00 to 9·00). The primary outcome occurred in 215 patients (65·15%) in the rhPro-UK group, compared to 214 patients (64·26%) in the alteplase group (rate difference [RD], 0·89; 95% confidence interval [CI], -6·52 to 8·29; P = 0·811), suggesting non-inferiority. Symptomatic intracerebral haemorrhage (sICH) occurred in five patients (1·52%) in the rhPro-UK group and in six patients (1·80%) in the alteplase group (RD, -0·28; 95% CI, -2·22 to 1·66; P = 1·000). Systemic bleeding within 90 days occurred more frequently in the alteplase group (141 [42·22%]) compared to the rhPro-UK group (85 [25·76%]) (RD, -16·46; 95% CI, -23·55 to -9·36; P < 0·0001). By 90 days, there were five intracranial haemorrhage-related deaths in each of the rhPro-UK group (1·52%) and alteplase group (1·50%) (RD, -0·02; 95% CI, -1·83 to 1·87; P = 1·000).
Interpretation: Intravenous rhPro-UK is non-inferior to alteplase within 4·5 hours of AIS onset. There were similar sICH but less systemic bleedings in the rhPro-UK group as compared with the alteplase group.
Trial Registration: This study was registered at ClinicalTrials.gov, number NCT03541668.
Funding: Tasly Biopharmaceuticals Co., Ltd.
Declaration of Interest: Tasly Biopharmaceuticals Co., Ltd. sponsored and funded this study, including providing investigational drug, funding to the investigator team, sponsoring investigator meeting, assisting with subject recruitment. RL, XML, LJH, JH, SPZ and MQL are full-time employees of Tasly. There are no other potential conflicts of interest relevant to this article to report.
Ethical Approval: The trial was approved by the Institutional Review Boards at each participating site, Xuanwu Hospital, Capital Medical University, Institutional Review Board, The First Bethune Hospital of Jilin University Institutional Review Board, The Affiliated Hospital of Xuzhou Medical University Institutional Review Board, Harrison International Peace Hospital Institutional Review Board, General Hospital Northern Theater Command Institutional Review Board, Inner Mongolia Autonomous Region People's Hospital Institutional Review Board, The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital, Huai’an Institutional Review Board, Xuzhou Central Hospital Institutional Review Board, First Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and
Technology Institutional Review Board, Affiliated Hospital of Inner Mongolia Medical University Institutional Review Board, Tangshan Gongren Hospital Institutional Review Board, The First Hospital of Hebei Medical University Institutional Review Board, Liaocheng People's Hospital Institutional Review Board, The Second Hospital of Hebei Medical University Institutional Review Board, Daqing Oilfield General Hospital Institutional Review Board, Baotou Central Hospital Institutional Review Board, Dalian Municipal Central Hospital Institutional Review Board, Cangzhou Central Hospital Institutional Review Board, Luoyang Central Hospital Institutional Review Board, The Fourth Affiliated Hospital of Harbin Medical University Institutional Review Board, Huai'an First People's Hospital Institutional Review Board, Liuzhou Worker's Hospital Institutional Review Board, The Neuropsychiatric Hospital of Jilin Province Institutional Review Board, Jiangxi Pingxiang People's Hospital Institutional Review Board, Taizhou Hospital of Zhejiang Province, People's Hospital of Deyang City Institutional Review Board, The Air Force Hospital from Northern Theater of PLA Institutional Review Board, Handan First Hospital Institutional Review Board, Tianjin Huanhu Hospital Institutional Review Board, Beijing Luhe Hospital, Capital Medical University, Institutional Review Board, The First Affiliated Hospital of Harbin Medical University Institutional Review Board, Nanjing Drum Tower Hospital Institutional Review Board, The First Affiliated Hospital of Xi'an Jiaotong University Institutional Review Board, The People's Hospital of Sichuan Province Institutional Review Board, The First Hospital of Changsha Institutional Review Board. Written informed consent was obtained from patients or their legal representatives before enrolment.
Keywords: acute ischemic stroke, thrombolytic, recombinant human prourokinase, alteplase
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