Proximal TEmporary oCclusion using balloon guide caTheter for Mechanical Thrombectomy (PROTECT-MT): study protocol for a multicenter randomized trial

Introduction

During the procedures of mechanical thrombectomy (MT), devices played an important role in the success of vascular recanalization. A balloon guide catheter (BGC) is an adjunctive device used to arrest and reverse flow by inflating the balloon at its tip, which allows for flow reversal in intracranial arteries during retrieval of thrombectomy devices by applying concomitant aspiration through its lumen (1). Multiple in vitro and animal studies show that BGC usage reduces distal emboli in case of clot fragmentation compared to conventional guide catheters (2). Some observational studies have also shown that the use of BGC improved the final reperfusion quality, shorten the procedure time, and may lead to better clinical outcomes in patients undergoing thrombectomy (3-10). Based on these findings, BGC usage during MT is recommended or preferred in current American and European guidelines (11,12).

However, high-level evidence data are still absent (13). While substantial observational pre-clinical and clinical data point towards a beneficial effect of BGCs, results of some other studies did not supported such findings (14-18). Moreover, some recent studies reported adverse outcome with the use of BGC compared with conventional guide catheter (19,20). These issues aroused debates on whether BGC should be routinely used in thrombectomy treatment (13).

Due to these practice heterogeneities and lack of high-level evidence data, we initiated Proximal TEmporary oCclusion using balloon guide caTheter for Mechanical Thrombectomy (PROTECT-MT) trial to assess the effectiveness and safety of BGC usage in MT for acute ischemic stroke (AIS) due to large vessel occlusion (LVO). We present this article in accordance with the SPIRIT reporting checklist (available at https://jni.amegroups.com/article/view/10.21037/jni-24-5/rc).

Methods

Study aims

This study aims to determine the effectiveness and safety of use of BGC as compared to conventional guide catheter on functional outcome [modified Rankin scale (mRS) score] in patients with AIS due to anterior circulation LVO.

Study design

This is a prospective, multicenter, randomized controlled, open-label, blinded outcome assessment trial involving eligible subjects to be recruited from 40–60 hospitals in China. Subjects who meet the eligibility criteria will be randomized to either intervention group (receiving treatment with BGC) or control group (receiving treatment with conventional guide catheter) (Figure 1). Follow-up would be conducted at 1, 7, and 90 days after thrombectomy (Table 1).

Figure 1 Flow chat in PROTECT-MT. PROTECT-MT, Proximal TEmporary oCclusion using balloon guide caTheter for Mechanical Thrombectomy; AIS, acute ischemic stroke; LVO, large vessel occlusion; mRS, modified Rankin scale.

Consent will be obtained upon a patient’s presentation to hospital prior to proceeding to cerebral angiography, with randomization undertaken after confirming the inclusion and exclusion criteria. The study will be conducted in compliance with local and international regulatory and ethical requirements, as well as the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Changhai hospital and ethics committee at each participating hospital. It was registered in ClinicalTrials.gov with identifier: NCT05592054.

Population

Subjects with AIS due to due to anterior circulation LVO confirmed by cranial imaging and are eligible for MT according to local guidelines will be enrolled into this study. The principal investigator at each site will be responsible for subject screening and enrollment. Detailed inclusion and exclusion criteria are shown as below.

Inclusion criteria: (I) age ≥18 years; (II) diagnosis of AIS with confirmed anterior circulation LVO [including intracranial segment of the internal carotid artery, and the first or proximal second segment (M1 or proximal M2) of the middle cerebral artery] by brain imaging; (III) to receive MT within 24 hours after AIS onset according to local guidelines; (IV) preoperative mRS score of 0–1; (V) signed informed consent form obtained from the subject (or approved surrogate).

Exclusion criteria: (I) intracranial hemorrhage confirmed by imaging; (II) known or suspected pre-existing (chronic) LVO in the symptomatic territory; (III) excessive vascular access tortuosity disables the use of BGC; (IV) intracranial stent implanted in the symptomatic territory that precludes the deployment/removal of the MT device; (V) any other condition that precludes the performing of MT procedure; (VI) occlusions in multiple vascular territories confirmed by computed tomography angiography (CTA) or magnetic resonance angiography (MRA); (VII) subjects who are pregnant; (VIII) subjects who are allergy to the contrast agent; (IX) subjects who refuse to cooperate or unable to tolerate interventional operation; (X) subjects whose expected lifetime are less than 90 days; (XI) subjects who are unlikely to participate in follow-up assessments according to the investigator’s judgement; (XII) any other condition that, according to the investigator’s judgement, not suitable for using of BGC.

Randomisation and blinding

Subjects will be randomized via an Internet-based randomization system in a 1:1 manner to treatment with BGCs (intervention group) or not (control group). The randomization sequence will use a minimization algorithm by investigators to ensure balance in key prognostic factors, according to stratifying variables of site of recruitment, preferred thrombectomy strategy (stent retriever vs. aspiration vs. stent retriever + aspiration) and time from symptom onset to recanalization (<6 vs. ≥6 h).

Both patient and treating physician will be aware of the treatment assignment. But outcome evaluation would be blinded. Information on outcome at 90 days will be assessed through standardized forms and procedures, by a trained investigator blinded for treatment allocation. Interviews will be recorded. Assessors who are blinded to the treatment allocation will perform assessment of outcome on the mRS on this information. Neuro-imaging will be also assessed by a core-laboratory blinded for treatment allocation. Information on treatment allocation will be kept separate from the main study database. The steering committee will be kept unaware of the results of interim analyses of efficacy and safety. An independent Data and Safety Monitoring Board (DSMB) statistician will combine data on treatment allocation with the clinical data to report to the DSMB.

Intervention

Subjects will be treated with thrombectomy based on the results of randomization. Subjects in intervention group would be treated with BGCs combined with conventional thrombectomy, while subjects in control group will be treated with conventional guide catheter combined with conventional thrombectomy.

For patients enrolled in this study, the guiding catheters were delivered via a coaxial system, or exchanging technique, into the target artery. Endovascular thrombectomy procedure was then performed according to the strategy selected for randomization, namely stent retriever, aspiration or combined usage of stent retriever and aspiration. For the stent retriever strategy, a suitable delivery microcatheter was navigated over a microwire across the occlusion site. A control super-selective angiogram was used to document the extent of the occlusion and thrombus. Then, the stent retriever device was deployed across the occlusion and withdrawn according to the instructions for use. When aspiration was used, the largest diameter aspiration catheter that the occluded vessel could accommodate was recommended. For the combination technique, stent retriever would be used with the intermediate catheter. BGC was inflated before withdrawal the clot, and vigorous aspiration was applied via the guide catheter until clot retrieval device is withdrawn from the body, per instructions for use guidelines.

Any BGC, stent retriever, intermediate or aspiration catheter approved by National Medical Products Administration were allowed, and were left to investigators’ discretion.

Results

Primary outcome

The primary outcome is patient functional outcome, defined as mRS score shift, at 90 days.

Secondary outcomes

(I) Dichotomized mRS at 90 days after the procedure (0–1 versus 2–6, 0–2 versus 3–6, 0–3 versus 4–6, 0–4 versus 5–6, 0–5 versus 6); (II) change in stroke severity (NIHSS score) at 24 hours post treatment; (III) change in stroke severity (NIHSS score) at 7 days post treatment or discharge (whichever occurs first); (IV) final infarction volume at 5–7 days post treatment; (V) technical success rate (defined as successfully navigating the guide catheter into the target vessel, and finishing the MT procedure without changing to another guide catheter); (VI) reperfusion outcome (eTICI 2b or greater, eTICI 2c or greater, eTICI 3) in final angiogram; (VII) reperfusion outcome (eTICI 2b or greater, eTICI 2c or greater, eTICI 3) after the first pass; (VIII) time from groin puncture to successful reperfusion (eTICI 2b or greater, eTICI 2c or greater); (IX) percentage of subjects with acceptable revascularization quality (eTICI 2b or greater, eTICI 2c or greater) within 45 min of access; (X) number of thrombectomy attempts (final); (XI) occurrence of emboli to a new territory.

Safety outcomes

(I) Deaths at 90 days (±14 days) post treatment; (II) intracranial hemorrhage, symptomatic intracranial hemorrhage or asymptomatic intracranial hemorrhage at 7 days post treatment or discharge (whichever occurs first); (III) other serious adverse events (SAEs) adjudicated by the Clinical Events Committee; (IV) any peri-procedural complications, including vessel dissection, arterial perforation, femoral access complications, contrast allergy, etc.

Cost outcomes

(I) Health-related quality of life using EQ-5D; (II) utility-weighted mRS scores; (III) duration of hospitalization; (IV) treatment cost.

Data collection and management

Electronic data capture (EDC) system will be used in this study, collected data will be entered into the electronic case report form (eCRF) by the investigator or authorized staff, who will receive extensive training prior to data entry. All personal privacy information (including subject names) would be confidential to protect the privacy of the subjects. The first monitoring visit following initiation and activation of the site took place within 7 working days of the first subject enrollment. Subsequent regular monitoring audits (at least every 6 months) are performed to ensure the accuracy and completeness of the data.

Primary outcome data were obtained from structured interviews that were performed in person or by telephone with the use of standardized forms; interviews were conducted by local trained physicians who were unaware of the trial-group assignments. Standardized written reports of each interview were provided to two members of an outcome committee, who verified the score by consensus. Clinical assessments were performed at baseline, at 24 hours after randomization, at 5 to 7 days or at the time of hospital discharge (whichever came first), and at 90 days (within a window of ±14 days). All the clinician assessors received both on-site and Web-based video training on how to perform the clinical assessments. Images were read by two readers, with consensus reached in case of discrepancies.

DSMB

An independent expert DSMB is responsible for reviewing the safety, ethics, and accumulating data for the study. The members are governed by a charter outlining their responsibilities, procedures, and confidentiality, for monitoring the efficacy and safety outcomes for early dramatic benefits or potential harmful effects, and to provide reports to the Trial Steering Committee with recommendations to continue, pause, or terminate recruitment. DSMB review unblinded data on recruitment, adherence to the protocol, primary and secondary outcomes, and SAEs, at regular intervals. A recommendation to discontinue the trial prematurely will be based upon there being clear evidence that the treatment provides protection or causes harm for an important clinical outcome.

Sample size

In a meta-analysis comparing BGC with conventional guide catheter, the use of BGC improved the proportion of functional outcome by 10.8% (21). In this study, based on a more conservative estimate, we assume the usage of BGC would improve the function outcome by 8%.

Based on the distribution of the mRS in the control group of the trial, which we derived from the intervention group of the MR CLEAN trial (22): mRS 0: 3%; mRS 1: 9%; mRS 2: 21%; mRS 3: 18%; mRS 4: 22%; mRS 5: 6% and mRS 6: 21%. We assumed a favorable treatment effect with a common odds ratio (cOR) of 1.43, corresponding to an 8% absolute increase in the rate of mRS scores of 0–2. In a simulation with 5,000 runs we computed the proportion of positive trials, for a given sample size. A sample size of 1,074 subjects is estimated to be able to demonstrate this treatment effect with 87% power and 5% type-1 error. This sample size also allows for 5% dropout rate and 5% crossover rate.

Statistical analysis

Analyses will be performed based on the intention-to-treat (ITT) principle. Baseline data by treatment allocation will be reported with statistical procedures. Missing baseline characteristics will be imputed using regression imputation as appropriate. The primary endpoint will be analyzed by means of an ordinal logistic regression. Pre-defined subgroups will be analyzed by testing for interaction between the specific baseline characteristic and treatment. Any reported SAE or discontinuation of assigned treatment due to an SAE will be classified using MedDRA. Statistical analyses will be detailed in the pre-specified Statistical Analysis Plan (shown in the https://cdn.amegroups.cn/static/public/jni-24-5-1.pdf).

The study consists of 2 interim analyses to be performed when 30% and 60% of the 90-day follow-up data have been collected. The independent DSMB will adopt the Haybittle-Peto rule, and α<0.001 in the interim analysis will be considered as statistically significant. Because 2 interim analyses will be performed, the significance level of α=0.0482 will be used for final analysis. The DSMB will monitor SAEs (e.g., death, spontaneous intracerebral hemorrhage, and neurological deterioration) periodically, and the occurrence of excessive SAEs will trigger discussion regarding termination of the study.

Progress to date

Recruitment started on February 7, 2023, in China. At a meeting of the DSMB on November 13, 2023, there were 329 patients randomized at 28 active sites in China. After reviewing primary outcome data available for 169 participants, they recommended suspension of recruitment due to safety concerns. Due to persistent concerns raised by the DSMB on further review of all available outcome data on April 18, 2024, the Trial Steering Committee stopped patient recruitment.

Role of the funding source

The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Discussion

PROTECT-MT is a randomized clinical trial with a PROBE design assessing the effectiveness of BGC versus conventional guide catheter in LVO-AIS patients treated with MT.

Compared with other trials evaluating the role of BGC in MT (23), our trial has some differences in the trial design, including inclusion/exclusion criteria, control arm setting, primary outcomes, etc. To better understand the effectiveness of BGC in the real world and allow for generalization of the study results, we set conventional guide catheter, rather BGC without inflation, as control arm, and we included a wide range of population. Essentially all patients eligible for MT with an anterior circulation occlusion according to local guidelines can be included in the trial (24). In addition, we set the 90-day mRS as primary outcome rather other surrogate marker to direct evaluating the impact of BGC on patient outcome, which resulted in a large sample size of our trial. The meta-analysis comparing BGC with conventional guide catheter suggested, the use of BGC improved the proportion of functional outcome by 10.8% (21). In this study, based on a more conservative estimate, we assume the usage of BGC would improve the function outcome by 8%. Based on that, a sample size of 1,074 subjects was calculated to demonstrate this treatment effect with 87% power and 5% type-1 error, which also allows for 5% dropout rate and 5% crossover rate.

Current reports indicated the effect of BGC may differ with primary techniques, while BGC seems effective in patients treated with stent retriever, controversies existed in patients treated with other techniques such as primary aspiration, and primary combined approaches (stent-retriever with distal aspiration) (14,15). In order to minimize the risk of bias related to differences in thrombectomy techniques in the control and intervention arms, we set the primary thrombectomy technique to ensure equal and balanced distribution of the three techniques in the BGC arm and the control arm.

Conclusions

PROTECT-MT is the largest RCT assessing the effectiveness of BGC as compared to conventional guide catheter on functional outcome in patients with AIS due to anterior circulation LVO. This trial will provide more reliable evidence and guide the clinical practice.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://jni.amegroups.com/article/view/10.21037/jni-24-5/rc

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-24-5/prf

Funding: This study was supported by Shanghai Hospital Development Center (SHDC2022CR019), the Biopharma Industry Promotion Center Shanghai (FW2023CYBG01), National Natural Science Foundation of China (82071278 & 82371313).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-24-5/coif). M.G. reported grants from Medtronic, Royalties or licenses from Microvention, and consulting fees from Medtronic, Microvention, Stryker, Mentice, Philips and Penumbra, outside the submitted work. P.Y. serves as the unpaid Executive Editor-in-Chief of Journal of Neurointervention. J.L. serves as the unpaid Editor-in-Chief of Journal of Neurointervention. This article was supported by Ton-bridge Medical Technology Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Changhai hospital and ethics committee at each participating hospital. Informed consent will be obtained from all individual participants or their surrogates.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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