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Rationale and design of ProUrokinase in Mild IsChemic strokE (PUMICE): a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial
  1. Yunyun Xiong1,2,3,
  2. Manjun Hao1,
  3. Yuesong Pan2,
  4. Chunmiao Duan1,
  5. Xueyan Feng1,
  6. Hao Li2,
  7. Na Wu1,
  8. Liyuan Wang1,
  9. Xia Meng2,
  10. Xingquan Zhao1,
  11. Yongjun Wang1,2
  12. On behalf of the PUMICE investigators*
  1. 1Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
  2. 2China National Clinical Research Center for Neurological Diseases, Beijing, China
  3. 3Chinese Institute for Brain Research, Beijing, China
  1. Correspondence to Dr Yongjun Wang; yongjunwang{at}ncrcnd.org.cn

Abstract

Background and purpose Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, that is non-inferior to alteplase in acute ischemic stroke. We aimed to investigate the efficacy and safety of rhPro-UK compared with standard medical treatment in acute mild ischemic stroke within 4.5 hours of symptom onset.

Methods and design Prourokinase in mild ischemic stroke is a multicentre, prospective, randomised, open-label, blinded-endpoint controlled trial. Patients who had an acute ischemic stroke within 4.5 hours from symptom onset and with baseline National Institutes of Health Stroke Scale (NIHSS) score ≤ 5 will be recruited. Patients will be randomly assigned (1:1) to receive intravenous rhPro-UK (35 mg) or standard medical treatment. The follow-up duration will be 90 days. The calculated sample size is 1446.

Study outcomes Primary efficacy outcome is an excellent functional outcome, defined as a modified Rankin Scale (mRS) score ≤ 1 at 90 days. Secondary efficacy outcomes include ordinal distribution of mRS at 90 days, mRS score ≤ 2 at 90 days, early neurological improvement at 24 hours (a decrease of NIHSS score ≥ 4 points compared with baseline or NIHSS score ≤ 1 point), Barthel index of 75–100 points at 90 days, quality of life at 90 days, and activities of daily living at 90 days. Safety outcomes are symptomatic intracranial haemorrhage within 36 hours, mortality at 90 days, moderate and severe systematic bleeding at 90 days, and adverse events/serious adverse events within 90 days.

Discussion This large phase III randomised clinical trial will answer the question of whether thrombolysis is beneficial for acute mild ischemic stroke, and may provide evidence for rhPro-UK in patients had an acute mild ischemic stroke within 4.5 hours of symptom onset.

Trial registration number NCT05507645

  • thrombolysis
  • ischaemic stroke
  • reperfusion
  • prourokinase

Data availability statement

Data are available upon reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/svn-2023-002673

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Recombinant human prourokinase (rhPro-UK) is a new generation of specific plasminogen activator, a thrombolytic agent that was non-inferior to alteplase in acute ischemic stroke with National Institute of Health Stroke Scale score of 4–25.

    WHAT THIS STUDY ADDS

    • The efficacy and safety of intravenous rhPro-UK versus standard medical treatment in patients who had a mild ischemic stroke within 4.5 hours.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • rhPro-UK may provide evidence for its use in patients who had a mild stroke within 4.5 hours of stroke onset.

    Introduction

    Mild stroke accounts for up to 50% of ischemic stroke.1 Currently, the standard treatment for non-cardiac mild ischemic stroke is aspirin combined with clopidogrel within 24 hours of onset, and cardioembolic mild ischemic stroke may use anticoagulants.2 However, about 30% of the patients still exhibit obvious neurological deficits at discharge.3 Previous post-hoc analysis of clinical trials or cohort studies suggest that mild ischemic stroke might benefit from intravenous thrombolysis without increasing the risk of intracranial haemorrhage, particularly in disabling stroke.4–8 Regarding non-disabling stroke, the preterminated Study of the Efficacy and Safety of Alteplase in Participants with Mild Stroke (PRISMS) showed that intravenous alteplase did not provide a 90-day functional benefit compared with aspirin, but rather increased risk of symptomatic intracranial haemorrhage (sICH).9 Recently, the ARAMIS (the Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke) study demonstrated that the dual antiplatelet therapy (DAPT) was non-inferior to alteplase in patients who had a mild non-disabling stroke with National Institute of Health Stroke Scale (NIHSS) score ≤ 5 within 4.5 hours of symptom onset.10 However, the benefit of intravenous thrombolysis for patients who had a disabling mild stroke lacks solid evidence, while for non-disabling mild stroke, large randomised controlled trials are also in need.

    As a new generation of specific plasminogen activators, recombinant human prourokinase (rhPro-UK) has been clinically used in thrombolytic therapy in acute myocardial infarction since 2011 in China.11 Prolyse (nasaruplase beta) is a glycosylated 411-amino acid single-chain proenzyme precursor of urokinase derived from transfected murine SP2/0 hybridoma cells. Single-chain rh-proUK is activated to 2-chain urokinase at the thrombus surface by fibrin-associated plasmin.12 Compared with alteplase, rhPro-UK does not neutralise with the proteolytic enzyme inhibitors in the blood, and it has specificity for embolism and thrombus without increasing systemic bleeding, in addition, its price is much less expensive than alteplase. The Prolyse in Acute Cerebral Thromboembolism II trial has demonstrated that intra-arterial rhPro-UK is beneficial for patients who had an acute ischemic stroke (AIS) due to middle cerebral artery occlusion within 6 hours of symptom onset.12 A phase II clinical trial showed that rhPro-UK 35 mg and 50 mg had similar excellent functional outcomes at 90 days, without increasing mortality or serious adverse events (SAEs).13 In addition, the PROST (The Efficacy and Safety of Recombinant Human Prourokinase in the Treatment of Acute Ischemic Stroke Within 4.5 Hours of Stroke Onset) study showed that rhPro-UK was non-inferior to alteplase and showed a lower rate of systemic bleeding in (NIHSS score of 4–25) patients who had an AIS within 4.5 hours of symptom onset.14

    Therefore, we aimed to perform a randomised clinical trial—the prourokinase in mild ischemic stroke (PUMICE) to explore the efficacy and safety of rhPro-UK (35 mg) in acute mild stroke (NIHSS ≤ 5) within 4.5 hours of symptom onset.

    Methods

    Study design

    PUMICE is a multicentre, prospective, randomised, open-label, blinded-endpoint (PROBE) controlled trial. We plan to recruit 100 trial centres in China in the PUMICE trial. Patients will be randomly assigned, in a 1:1 ratio, to receive rhPro-UK or standard medical treatment using centralised simple randomisation. The follow-up duration will be 90 days (online supplemental file 1).

    Supplemental material

    Patient population

    Adult patients who had a mild acute ischemic stroke (defined as NIHSS ≤ 5) within 4.5 hours from last known well and with premorbid modified Rankin Scale (mRS) score ≤ 1 will be enrolled into the PUMICE trial. Patients who intend to have endovascular treatment or have rapidly improving symptoms will be excluded. Figure 1 shows details of inclusion and exclusion criteria.

    Figure 1
    Figure 1

    Inclusion and exclusion criteria.

    Baseline assessment

    We will collect information on demographics, medical history, medications, thrombolytic time measures and laboratory tests. Baseline stroke severity (NIHSS score) and premorbid mRS score will be assessed by certified and well-trained clinicians. CT is required to rule out cerebral haemorrhage, large infarct core, or brain masses.

    Randomisation and blinding

    Participants will be randomly assigned, in a 1:1 ratio, to receive rhPro-UK or standard medical treatment. The randomisation sequence will be generated automatically in a centralised computer at the contract research organisation on day 1. All endpoints in each centre will be evaluated by qualified study physicians who are blinded to treatment allocations.

    Treatment intervention

    Intervention group: rhPro-UK (5 mg per vial, 7 vials with 35 mg in total)

    15 mg (three vials) of rhPro-UK will be dissolved in 10 mL of saline and given intravenous bolus within 3 min, the remaining 20 mg (four vials) will be dissolved in 90 mL of saline, and will be administrated via intravenous drip within 30 min.

    Control group: standard medical treatment

    Standard medical treatment with antiplatelet or anticoagulant treatment at the discretion of local investigators will be given to the control group according to the Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018.2

    Concomitant management

    All the enrolled patients are requested to be admitted into stroke units or intensive care units if necessary. In the rhPro-UK group, participants will be prohibited from receiving any drugs that may increase the risk for bleeding within 24 hours, including antiplatelets, anticoagulants, fibrinogen-lowering drugs, other thrombolytic drugs and platelet function inhibitors (indomethacin, butalidon, Ozagrel). In-hospital management for all participants will be performed according to the Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018.2

    Follow-up

    Study visits include the screening period (0–4.5 hours before thrombolytic therapy), 0 hours (thrombolytic therapy), 24 ± 6 hours, 36 ± 6 hours, 7 ± 2 days or before discharge, and 90 ± 7 days. (Figure 2) Brain CT should be performed during the screening period. At 24 hours of randomization, repeated brain CT should be performed to detect haemorrhagic transformation to determine the secondary prevention strategy. The follow-up CT will be performed within 24–36 hours to determine sICH for patients who have symptoms or signs of deterioration. Figure 3 shows data collection of clinical information, including the neurological examination (NIHSS and mRS score), vital signs, concomitant medications and laboratory tests, adverse events (AEs) and SAEs at baseline and during follow-up visits.

    Figure 2
    Figure 2

    Study flow chart. mRS, modified Rankin Scale; NIHSS, National Institute of Health stroke Scale; rhPro-UK, recombinant human prourokinase.

    Figure 3
    Figure 3

    Trial assessment flow chart.

    If SAEs or suspicious and unexpected serious adverse reactions occur, investigators should adhere to Good Clinical Practice guidelines. The Endpoint Adjudication Committee will adjudicate the reports.

    Outcomes

    The primary and secondary outcomes, including efficacy outcomes and safety outcomes, are shown in figure 4.15 16

    Figure 4
    Figure 4

    Study outcomes.

    Committees

    The Steering Committee, independent data and safety monitoring boards, as well as the endpoint adjudication committee, will be organised to ensure the trial’s academic quality, implementation and endpoint evaluation. The responsibility of these committees is the same as that of the Tenecteplase Reperfusion Therapy in Acute Ischemic Cerebrovascular Events III trial which was published previously.17

    Sample sizes and statistical analysis

    Sample size

    There are two arms, rhPro-UK 35 mg arm, and the standard medical treatment arm, with a group allocation ratio of 1:1. The primary efficacy outcome is mRS score ≤ 1 at 90 days. According to the CNSR-III (the Third China National Stroke Registry) cohort study, the rate of mRS score of 0–1 at 90 days in patients who had a mild stroke (NIHSS ≤ 5) without thrombolysis was 83%.18 In the combined analysis of the Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events trial and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke trial, the rate of mRS ≤ 1 at 90 days in patients who had a mild stroke was 90%.19 Therefore, we assume that the rate of mRS ≤ 1 at 90 days in the standard medical treatment group in this clinical trial will be 85%, and the absolute rate difference in the rhPro-UK group is 5%. Based on these assumptions, with the one-sided test α = 0.025, the power of 1-β = 0.8, the minimum sample size required for this clinical trial is 1372 using PASS 16.0 software (NCSS, LLC, USA). Assuming a 5% attrition rate, we set the final calculated sample size as 1446.

    Statistical analysis

    The efficacy assessment will be carried out on both the full analysis set and per protocol set. Multiple imputations will be used to fill in the missing efficacy data. Safety outcomes will be evaluated in the safety set with no imputation performed for missing safety data. The primary efficacy outcome will be analysed by using the Cochran-Mantel-Haenszel test, adjusted for centre effects, with a calculation of relative risk or risk difference and 95% CI. Subgroup analyses for primary efficacy outcome will also be conducted based on age (< 75 vs ≥ 75 years and <80 vs ≥ 80 years), stroke severity at baseline NIHSS score < 3 and 3–5 (both inclusive), time from onset to treatment 0–3.0 hours (inclusive), 3.0–4.5 hours (inclusive), diabetes and hypertension. Secondary outcomes will be analysed using similar methods as the primary outcome. Regarding the safety outcomes between groups, the number of cases, frequencies and rates of AEs in each group will also be analysed statistically, and a detailed list of AE descriptions will be provided. χ2 or Fisher’s exact tests will be used to compare differences in safety outcomes between groups. All statistical analyses will be processed by SAS V.9.4 or higher version (SAS Viya, USA).

    Version modifications

    We had two minor modifications to the protocol. In version 1.1, we modified the block stratified randomisation to centralised simple randomisation from protocol version 1.0. In version 1.2, we deleted the dosage recommendation for clopidogrel and aspirin, and recommended the use of antiplatelet therapy or anticoagulants at the discretion of local investigators.

    Discussion

    Whether patients who had a mild stroke could benefit from intravenous thrombolysis lacks strong evidence. Acute stroke guidelines recommended thrombolysis in disabling stroke mainly based on post-hoc analysis of clinical trials and experts’ opinions,20 although non-disabling stroke seems to have a consistent conclusion of receiving no benefit from thrombolysis when compared with DAPT, more phase III trials are in need. Our trial is a phase III, randomised clinical trial of rhPro-UK in patients who had an acute mild ischemic stroke within 4.5 hours time window. This will allow us to exclusively answer the question of whether intravenous thrombolysis is beneficial for patients who had an acute mild ischemic stroke within the standard time window.

    Several retrospective analysis suggests that mild ischemic stroke may benefit from intravenous thrombolysis without increasing additional risk of intracranial haemorrhage.5–9 21 A post-hoc analysis of the third international stroke trial-3 showed that within 3 hours of onset, patients with baseline NIHSS ≤ 5 in the thrombolytic group had a significant increase in the proportion of alive and independence than those in the control group, but no significant difference in the proportion of good outcomes between the two groups.5 A meta-analysis of nine thrombolysis trials showed that, regardless of the severity of stroke, intravenous alteplase treatment within 4.5 hours of onset can significantly improve patients’ functional outcomes. It is worth noting that the proportion of patients with NIHSS≤4 in this study was only 10%.21 Apart from trial post-hoc analysis, a retrospective analysis from the Get with The Guideline stroke registry database included 5910 patients with NIHSS≤5 who received intravenous alteplase within 4.5 hours of onset and showed low sICH risk and low mortality, with around 70% able to ambulate independently and return directly home at discharge.6 Other real-world studies also found that thrombolysis was associated with better functional outcomes (mRS 0–1 at 90 days) and good quality of life.7 8

    Whether non-disabling stroke benefits from intravenous thrombolysis is a hot topic in the past 10 years. The PRISMS trial was terminated early due to slow patient recruitment and no definitive conclusions were obtained.9 The recent ARAMIS trial found that DAPT was non-inferiority to intravenous alteplase in achieving an excellent functional outcome (mRS score 0–1) at 90 days.10 However, in order to provide a high level of evidence for changing the guidelines, at least one more Randomized Controlled Trial (RCT) focusing on non-disabling stroke is needed.

    To answer whether mild ischemic stroke could benefit from thrombolysis, currently, to our best knowledge, the PUMICE trial the unique RCT, including disabling and non-disabling together. In addition, as a new generation of specific plasminogen activators, rhPro-UK was less expensive than alteplase and tenecteplase, with lower risk for systemic bleeding.14 22 The recent phase III PROST trial demonstrated that intravenous rhPro-UK was non-inferior to alteplase with a similar rate of sICH but fewer cases of systemic bleeding in patients who had an AIS with an NIHSS score of 4–25 presenting within 4.5 hours of symptom onset.14

    In terms of thrombolysis in mild ischemic stroke, the TEMPO-2 (Thrombolysis With Low Dose Tenecteplase vs Standard of Care in Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion, NCT02398656) trial is comparing tenecteplase to standard medical treatment in patients who had a mild ischemic stroke (NIHSS≤ 5) or a transient ischemic attack with proven large vessel occlusion within 12 hours of symptom onset. This trial also does not require disabling or non-disabling, but requires large vessel occlusion, therefore, a majority of patients will be disabling stroke.

    Our study has several limitations. First, given that we are unable to provide a reliable source of rhPro-UK placebo, we could not choose a double-blind, placebo-controlled trial design for this trial, but the PROBE design also requires that the outcome evaluations need to be blinded, which can also provide convincing conclusion based on the PROBE design. Second, we will not detect large vessel occlusion in patients since CT angiography is not part of the screening process before thrombolysis therapy according to current guidelines in China.2 Third, our trial will be conducted entirely in China, so the reliability of the conclusions in other countries and regions needs to be verified through further clinical trials. Fourth, we did not distinguish between disability and non-disability mild ischemic stroke, mainly because we believe that there is a lack of evidence on whether thrombolysis should be performed for patients with mild ischemic stroke without consensus on the definition of disability stroke. Hence, we will further analyse this variable in a post-hoc analysis.

    In conclusion, PUMICE will be the first RCT to provide the efficacy and safety of rhPro-UK in patients who had a mild ischemic stroke within 4.5 hours of symptom onset.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and the principles of the Declaration of Helsinki. All participants gave informed consent before taking part. This study obtained Ethics approval from the Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University with number KY2022-120-04.

    Acknowledgments

    The Steering Committee: Yongjun Wang, Pooja Khatri (USA), Anding Xu, Qiang Dong, and Yun Xu. Data and Safety Monitoring Board: Dongsheng Fan, Bin Peng, Ying Xian (USA). Independent statistician: Aoming Jin.

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    Supplementary material

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Contributors Obtained funding, concept and design: YW. All authors contributed to the study design. Drafting of the manuscript: YX. Critical revision of the manuscript for important intellectual content: YW. Statistical analysis: YX, HL, YP. All authors approved the submitted version.

    • Funding This study was funded by TASLY BIOPHARMACEUTICALS CO.,LTD. with the investigation drugs provided for free.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.