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Abstract
Introduction Successful reperfusion does not always lead to good neurological outcomes and impaired microcirculation can be one of the underlying causes. Intra-arterial alteplase after mechanical thrombectomy (MT) may improve microcirculation contributing to neurological recovery, but prospective randomised studies are still needed to validate its efficacy and safety. We aim to assess the efficacy and safety of intra-arterial alteplase after MT for acute ischaemic stroke (AIS) with large-vessel occlusion (LVO).
Methods and analysis The Intra-arterial Alteplase for Acute Ischaemic Stroke After Mechanical Thrombectomy (PEARL) study is a multicentre, prospective, open-label, blinded-endpoint, randomised controlled trial. We consecutively screen AIS patients with anterior circulation LVO and National Institute of Health Stroke Scale of 6–25, who reach stable expanded Thrombolysis in Cerebral Infarction scores of 2b50-3 on angiography after MT. Eligible participants are 1:1 randomly assigned to the experimental group and the control group. Participants in the experimental group will receive intra-arterial alteplase (0.225 mg/kg and a maximum dose of 20 mg) after MT and standard medical treatment, while those in the control group will receive standard medical treatment alone after the procedure. The primary outcome is the proportion of patients with a 90-day modified Rankin scale of 0–1. A total of 324 participants are required to test the superiority hypothesis with 80% power at a two-tailed significance level of 0.05.
Ethics and dissemination This study has been approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2023-390-02) and will be conducted following the Declaration of Helsinki. Ethical approvals have been obtained separately for all centres participating in the study. Study results will be published in peer-reviewed academic journals.
Trial registration number NCT05856851.
- Stroke
- Clinical Trial
- China
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STRENGTHS AND LIMITATIONS OF THIS STUDY
This is the multicentre, open-label, blinded-endpoint, randomised controlled trial in patients with anterior circulation large-vessel occlusion that assesses the efficacy and safety of intra-arterial alteplase after mechanical thrombectomy.
Microcatheters will be placed proximal to the occlusion site rather than distal, to expand the extent of microcirculation that could be improved, which is expected to yield better efficacy.
Since the trial will be conducted in China, where the population is mainly Han Chinese, it may limit the generalisability of the study result.
Introduction
Acute ischaemic stroke (AIS) has become one of the most common causes of death and disability.1 2 The burden of AIS will continue to increase with the ageing of the population, while by 2050 there will be >1.5 billion people aged 65 years or older worldwide, resulting in a heavy social and economic burden.3 Intravenous thrombolysis (IVT) is an effective treatment for AIS, but for those caused by large-vessel occlusion (LVO) and cardiogenic embolism, the reperfusion rate of IVT is low and the therapeutic effect is poor.4 5
Rapid revascularisation to restore reperfusion to ischaemic tissues is essential for a good prognosis in patients with AIS-LVO.6 Previous studies have demonstrated that mechanical thrombectomy (MT) can significantly increase the reperfusion rate and improve clinical outcomes of AIS-LVO.7–9 However, successful revascularisation of LVO does not ensure the effective reperfusion of the distal microvascular bed. Although the reperfusion rate after MT reaches >70%, the functional independence rate at 90-day follow-up is <50%.10 The poor reperfusion of the microcirculation may be an important reason for the ineffective reperfusion in LVO.11
The Chemical Optimisation of Cerebral Embolectomy (CHOICE) study was the first trial to assess the efficacy of intra-arterial thrombolysis in LVO-AIS with successful reperfusion after MT, and they found that intra-arterial alteplase, compared with placebo, increased the proportion of excellent outcome at 90 days measured by the modified Rankin Scale (mRS) of 0–1 and did not increase the risk of symptomatic intracranial haemorrhage (sICH) and mortality.12 However, the CHOICE trial was terminated prematurely due to placebo shortages and slow enrolment as a result of the COVID-19 pandemic, leading to only 60% of the planning sample size being enrolled, which might have overestimated the efficacy of intra-arterial alteplase in functional recovery in patients with successful reperfusion. In addition, considering that the CHOICE study was only conducted at seven centres in Catalonia, Spain, and mainly recruited the White population, whether intra-arterial alteplase would be effective in patients from Eastern countries was still unknown.
Accordingly, we designed this multicentre, prospective, open-label, blinded-endpoint, randomised controlled trial to assess the efficacy and safety of intra-arterial alteplase after MT in improving neurological outcomes for AIS with LVO. We hypothesised that intra-arterial alteplase after MT would be effective and show clinically meaningful benefits in neurological recovery at 90-day follow-up and not significantly increase the risk of sICH and mortality.
Methods
Design
The Intra-arterial Alteplase for Acute Ischaemic Stroke After Mechanical Thrombectomy (PEARL) study is an investigator-initiated, multicentre, prospective, open-label, blinded-endpoint, randomised controlled trial conducted at 28 stroke centres in China (figure 1). The objective of the PEARL trial is to test the superiority hypothesis of intra-arterial alteplase after MT, compared with standard medical management, in improving neurological outcomes for AIS with anterior circulation LVO. The study design has been summarised in figure 2.
Study site distribution.
Study design of PEARL trial. AIS, acute ischaemic stroke; ASPECTS, Alberta Stroke Program Early CT Score; CTA, CT angiography; CTP, CT perfusion imaging; EQ-5D-5L, EuroQoL 5-Dimensions 5-Level Questionnaire; eTICI, expanded Thrombolysis in Cerebral Infarction; ICA, internal carotid artery; LVO, large-vessel occlusion; MRA, magnetic resonance angiography; mRS, modified Rankin Scale; MT, mechanical thrombectomy; NCCT, non-contrast CT; NIHSS, National Institute of Health Stroke Scale; PWI, perfusion-weighted imaging.
Study population
Patients with anterior circulation LVO and successful reperfusion after MT, defined as a stable expanded Thrombolysis in Cerebral Infarction (eTICI) score of 2b50-3 on digital subtracted angiography (DSA), would be consecutively screened for eligibility. The participant should be willing and sign informed consent to participate in the trial (online supplemental file). The detailed eligibility criteria are as follows:
Supplemental material
Inclusion criteria
Aged 18 years or older.
Clinical diagnosis of AIS.
Time from symptom onset to randomisation within 24 hours, including wake-up stroke or no-witness stroke; the onset time refers to ‘Last Known Well’ (LKW).
CTA or MRA confirmed occlusion of the intracranial segment of the internal carotid artery (ICA), or M1 or M2 segment of the middle cerebral artery; stable eTICI score of 2b50-3 after MT, with or without IVT. Patients with an eTICI score of 2b50-3 on the diagnostic cerebral angiography before MT are also eligible for the study.
Baseline National Institute of Health Stroke Scale (NIHSS) of 6–25.
Non-contrast CT/Diffusion Weighted Imaging (DWI)-MRI Alberta Stroke Program Early CT Score (ASPECTS) ≥6.
Prestroke mRS score ≤1, or mRS >1 but not related to neurological disease (eg, amputation and blindness).
Signed informed consent.
Exclusion criteria
Contraindication to recombinant human tissue plasminogen activator (except time to therapy).
Planned use of dual antiplatelet therapy within the first 24 hours after MT.
Angiographic evaluation showing dissection, severe stenosis or complete occlusion of the carotid artery, which requires the use of carotid artery stents during the endovascular procedure.
Suspected cerebral vasculitis based on medical history and/or angiographic evaluation.
Women who are pregnant or breastfeeding.
Participation in other clinical trials.
Preoperative intracranial haemorrhage confirmed by cranial CT or MRI.
Known genetic or acquired bleeding disposition with anticoagulation factor deficiency.
Coagulation disorder with International Normalised Ratio (INR) >1.7 or use of new oral anticoagulants (within 48 hours of symptom onset).
Platelet count <50×109 /L.
Suspected vascular occlusion as a result of infective endocarditis.
Known severe renal insufficiency with glomerular filtration rate <30 mL/min or blood creatinine >220 µmol/L (2.5 mg/dL).
Severe allergy to contrast (non-mild rash allergy) or absolute contraindication to iodine contrast.
Suspected aortic dissection.
Previous parenchymal organ surgery or biopsy in the last 1 month.
Any active or recent bleeding (gastrointestinal, urinary tract bleeding, etc) in the last 1 month.
Systolic blood pressure (SBP) >185 mmHg or diastolic blood pressure (DBP) >110 mmHg refractory to treatment.
Anticipated life expectancy <6 months (eg, malignancy, severe cardiopulmonary disease, etc).
Any condition that, in the judgement of the investigator, makes the patient unsuitable for this study or where this study may impose a significant risk to the patient (eg, inability to understand and/or comply with study procedures and/or follow-up due to psychiatric disorders, cognitive or emotional impairment).
Screening, randomisation and intervention
The screening will take place immediately after the patient arrives at the hospital. All patients with anterior circulation LVO stroke will be screened. Eligible patients who agree to participate in the study will sign informed consent and baseline information will be recorded in detail, including demographics data, medical history, physical examination, concomitant medications, blood tests on organ function, electrocardiography and brain imaging (CT or MRI). The investigator should complete a screening form including all subjects screened, which will be used to judge the representativeness of the patients enrolled at the different centres.
All patients will undergo standard endovascular treatment, either bridge or direct MT, following the usual practice of each participating site. Eligible patients will be randomly assigned into the experimental and control groups to receive either intra-arterial alteplase or only standard medical management after MT at a ratio of 1:1 stratified by centre and whether IVT before MT (yes or no), using the block randomisation method to generate the allocation sequence. The interactive online central randomisation system with the allotted sequences inside is prepared by independent statisticians who are not involved in study recruitment. The study drug (alteplase) is open-label, but outcome assessors and statistical analysts will remain unaware of group allocation.
According to the latest guidelines, all participants will receive standard medical management after the procedure. Participants in the experimental group will receive intra-arterial alteplase (0.225 mg/kg and a maximum dose of 20 mg) after MT. 15 min after the start of intra-arterial thrombolysis, the infusion will be stopped and an angiogram will be performed to assess the eTICI score. Participants allocated to the control group will only receive standard medical treatment without intra-arterial alteplase after MT.
All concomitant drugs are recorded by the investigators. To minimise the risk of cerebral haemorrhage, the use of heparin is not recommended before and during the procedure (except for the maintenance of surgical access), and intravenous heparin is forbidden until the brain imaging at 24±12 hours follow-up confirms the absence of cerebral haemorrhage. The reasons will be recorded in detail if the patient requests to withdraw from the trial.
Outcomes
The primary outcome is the proportion of patients with a 90-day mRS of 0–1. The mRS is a widely used scale to evaluate functional recovery after stroke, being coded from 0 (no symptoms at all) to 5 (severe disability) and 6 (death). A score of 0–1 indicates an excellent outcome (disability-free). The secondary outcomes include the change of infarct core volume from baseline to day 7±1 or discharge assessed by non-contrast CT, the volume of Tmax >6 s on CT perfusion (CTP) imaging from baseline to 24±12 hours after randomisation, the proportions of mRS 0–2 and 0–3 at 90 days, the shift analysis of 90-day mRS, the proportion of patients with NIHSS 0–1 or ≥10 points reduction at 48 (±12) hours and quality of life at 90 days measured by EuroQoL 5-Dimensions 5-Level. The 90-day mRS will be evaluated by an independent follow-up commissioner who will not be aware of group allocation through standardised telephone interviews and be reconfirmed by the independent outcome adjudication committee composed of non-investigators.
The primary safety outcome is sICH within 36 hours (according to Heidelberg criteria). The secondary safety outcomes include any ICH within 36 hours (according to Heidelberg criteria) and mortality within 90 days.
Follow-up procedures
Study visits will occur at 24±12 hours, day 7±1 or at discharge (whichever occurs first), and day 90±7. The follow-up schedule is displayed in table 1.
Study visits
Safety monitoring
Adverse events (AEs) include any adverse medical events, regardless of whether associated with interventions or not, that occur during the study, either self-reported by participants or observed by investigators. All information about AEs will be recorded, and whether the unexpected AE is associated with a pre-existing condition, intra-arterial alteplase administration, the MT procedure, intercurrent condition, incidental finding or others, will be recorded in detail and discussed by investigators. Severe AEs (SAEs) are defined as the AEs that result in death, life-threatening status, prolonged in-hospital time and disability. All SAEs will be reported to the local ethics committee within 24 hours of being observed. Baseline laboratory tests, vital signs, physical exams and imaging data are obtained to ensure that eligibility criteria are met. Follow-up (12–36 hours and 6–8 days) neuroimaging (MRI or CT) is required to detect haemorrhage.
Sample size determination
The primary efficacy outcome is the proportion of 90-day mRS of 0–1. The CHOICE study found that the proportion of 90-day mRS scores 0–1 in the control group was 40.4%, and the experimental group had an 18.6% improvement in the primary outcome.12 Given that the CHOICE study stopped early and may have overestimated efficacy, we assumed a 16% improvement in the proportion of 90-day mRS scores 0–1 in the experimental group compared with that in the control group, with a statistical power of 80%, a two-sided test level of 0.05, and a drop-out rate of 5%; therefore, a total of 324 participants will be enrolled, and 162 participants will be needed for each group.
The interim analysis will be performed when half of the participants have completed the 90-day follow-up visits (162 participants). The test levels for the interim and final analyses will be two-sided test levels of 0.003 and 0.049, respectively, using the O'Brien-Fleming method to avoid type I error inflation.
Statistical analysis plan
All participants who are randomly assigned will be included in the full analysis set (FAS) following the intention-to-treat (ITT) principle. The FAS is the primary efficacy evaluation sample for this trial. Participants who complete intra-arterial alteplase infusion following the protocol or without serious protocol violations will be included in the per-protocol set (PPS). The serious protocol violations include but are not limited to receiving treatment that seriously interferes with the efficacy evaluation before or after enrolment (eg, any endovascular therapeutic operations other than intra-arterial alteplase after randomisation), poor adherence, the follow-up that seriously exceeds the time window, etc. The PPS is the secondary analysed population for efficacy evaluation; however, any inconsistencies in the FAS results will require further detailed analyses. The safety analysis set defines all participants treated with intra-arterial alteplase.
The analysis will follow the ITT principle. Participants who have undergone randomisation will be included in the analysis. The difference in the proportion of 90-day mRS 0–1 between the two groups will be presented as the rate difference and its 95% CI. The χ2 test or Fisher’s exact test will be used to test whether there will be a statistically significant difference in the primary outcome between the two arms and to calculate the p value, and for the secondary and safety outcomes, χ2, Fisher’s exact, Student’s t- or Wilcoxon tests will be applied according to the types and distributions of the indexes. The p values of the secondary outcomes will not be corrected and should therefore be considered exploratory results. Moreover, a binary logistic regression analysis on the primary outcome adjusted for age, sex and centre and whether IVT will serve as a sensitivity analysis.
The primary efficacy outcome will be further assessed in the preplanned subgroup analyses. All participants in the FAS will be stratified by age (18–65 years or ≥66 years), IVT before MT (with or without), stroke severity before randomisation (NIHSS <16 or ≥16), culprit vessel (internal carotid artery or middle cerebral artery), baseline glucose level (<100 mg/dL or ≥100 mg/dL), baseline ASPECTS (6–8 or 9–10) and times of MT manoeuvres (<3 or ≥3).
Statistical analyses will be performed by independent statisticians unaware of the group allocation. The interim analysis will be performed when the 162 participants (50% of the total sample size) complete the study. The interim and final analysis tests will be adjusted for test level using the O'Brien-Fleming method, corresponding to a two-sided test level α of 0.003 (the interim analysis) and 0.049 (the final analysis), respectively. The Data and Safety Monitoring Board (DSMB) will decide on the continuation or termination of the study based on the interim analysis.
Trial status
This trial was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University on 27 April 2023 and registered on 12 May 2023 at www.ClinicalTrials.gov (NCT05856851). The first patient was enrolled on 1 August 2023.
Patient and public involvement
No patients or the public were involved in the design, conduct, reporting and dissemination plans of this research.
Ethics and dissemination
This study has been approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (SYSKY-2023-390-02) and all local institutional review boards. The study will be conducted per the Declaration of Helsinki and relevant local regulations. Informed consent will be obtained from all participants or their legal representatives prior to enrolment (online supplemental file). The findings of this randomised controlled trial will be published in a peer-reviewed clinical journal for widespread publication.
Study organisation
The steering committee will oversee the trial and provide academic guidance. Safety outcomes, AEs and SAEs will be reviewed by the Clinical Events Adjudication Committee. Imaging assessments will be conducted by the independent imaging core lab. The outcome adjudication committee will reconfirm the outcomes. The DSMB, constituted by non-investigators and an independent statistician, will meet regularly to monitor the trial’s progress, maintain patient safety and make recommendations for the continuation or termination of the trial.
Discussion
Whether intra-arterial alteplase after successful reperfusion is effective remains unknown. The first completed CHOICE trial found that intra-arterial alteplase, compared with placebo, increased the likelihood of excellent neurological outcome and did not increase the risk of sICH and mortality.12 However, the early termination and imbalance between the groups of CHOICE may have overestimated the efficacy, and the lack of an oriental population also limits its generalisability.
Currently, many trials are investigating the efficacy and safety of intra-arterial thrombolysis during or after MT in patients with AIS-LVO.13 Ongoing trials focusing on this topic have been summarised in table 2. The PEARL study is an investigator-initiated, prospective, open-label, blinded-endpoint, randomised controlled trial and is currently the only study that tests the efficacy of intra-arterial alteplase after successful reperfusion of patients with anterior circulation AIS-LVO by applying a randomised-controlled design in China, which is expected to offer high-level evidence for clinical practice in this Chinese population. Although prior studies have found that tenecteplase (TNK) was not inferior to alteplase for IVT,14–17 there is a lack of evidence on its safety and efficacy for intra-arterial thrombolysis. Therefore, we chose alteplase, rather than TNK, as our studied drug.
Ongoing trials investigating intra-arterial thrombolysis during or after mechanical thrombectomy
This study has several strengths. First, the trial is rigorously designed as a multicentre, prospective, open-label, blinded-endpoint randomised controlled trial, ensuring a high methodological rigour and minimising bias. The study’s focus on an Asian population fills a significant gap in existing research. Additionally, including preplanned subgroup analyses, such as comparing occluded vessel types, will provide valuable insights into the intervention’s varying effects in diverse clinical scenarios. The use of imaging techniques, including changes in infarct core volume and the volume Tmax ≥6 s on CTP, further strengthens its potential to elucidate the mechanisms underlying the intervention’s efficacy.
This study also has several limitations. Although the 16% superiority margin used for sample size estimation has been adjusted from the CHOICE trial results, it may still be overly optimistic for an Asian population, potentially resulting in an underpowered study if the actual effect size is smaller than expected. Moreover, the protocol specifies that microcatheters will be placed proximal to the occlusion site rather than distal, with the aim of improving microcirculation and achieving better efficacy. While focusing on a Chinese population enhances the study’s regional relevance, it may also limit the generalisability of the findings to other ethnic groups or regions. Additionally, the open-label design introduces the possibility of bias; however, this will be addressed by employing blinded outcome adjudicators, standardised assessment protocols, an independent adjudication committee and statistical sensitivity analyses to ensure objective and reliable results.
Ethics statements
Patient consent for publication
Acknowledgments
The authors thank in advance all the patients, investigators, caregivers and institutions participating in this study.
References
Supplementary materials
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
XY, XH, DP, YX and HP contributed equally.
Contributors Conceived and designed the study: YT and YL. Writing–drafting: XY, XH, DP, YX and HP. Writing–revising: KL, MZ, YZ, YC, BH, HZ, JL, HH, HS, YL and YT. Obtain funding: YT, YL, XY, YZ and YC. All authors approved the submission of this manuscript. Guarantors: YT and YL.
Funding This work is supported by STI 2030 Major Projects (2022ZD0211600), National Natural Science Foundation of China (81925031, 82330099), the Key-Area Research and Development Program of Guangdong Province (2023B0303040003), Science and Technology Program of Guangzhou (2023A03J0708), and Sun Yat-sen Memorial Hospital Clinical Research 5010 Program (SYS-5010Z-202302) to YT; National Natural Science Foundation of China (82371369) and Sun Yat-sen Memorial Hospital Clinical Research 5010 Programme (SYS-5010–2 02 402) to XY; National Natural Science Foundation of China (82304120) to YZ; Sun Yat-sen Pilot Scientific Research Fund (SYSQH-II-2024–04) to YC. This work is also supported by Shenzhen Key Medical Discipline Construction Fund (SZXK074).
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Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
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