Safety and efficacy of remote ischemic conditioning combined with endovascular thrombectomy for acute ischemic stroke due to large vessel occlusion of anterior circulation: A multicenter,randomized,parallel-controlled clinical trial (SERIC-EVT): Study protocol

Design

Safety and efficacy of remote ischemic conditioning combined with endovascular thrombectomy (SERIC-EVT) is a multicenter, randomized, parallel-controlled, and blinded endpoint clinical trial that evaluates the efficacy and safety of RIC in patients with AIS who underwent EVT. This study was approved by the ethics committee of the First Hospital of Jilin University and each study center involved. The trial is conducted in compliance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use-Good Clinical Practice Guidelines (ICH-GCP) and the Declaration of Helsinki (revised 2013).

Patient population

All 498 patients, 249 in the control group and another 249 in the treatment group, will be recruited from 10 hospitals that are qualified to perform EVT from the Jilin Province Stroke Emergency Maps in Jilin Province, Northeast China. ¹⁴ Investigators from the 10 hospitals will be informed of the study design and flow of our trial prior to enrollment. Figure 1 shows the flow of patient enrollment. The inclusion and exclusion criteria are presented in Table 1. All participants or their legal representatives will provide written informed consent.

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Figure 1.

Patient enrollment flowchart. eTICI: the expanded Thrombolysis in Cerebral Infarction; RIC: remote ischemic conditioning; CT: computed tomography; AEs: adverse events.

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Table 1.

Patient inclusion and exclusion criteria.

Inclusion criteria
1. Age ⩾18 years, male or female 2. Diagnosis of acute ischemic stroke due to large vessel occlusion of anterior circulation (large artery occlusion confirmed by head CTA or DSA) and history of emergent endovascular thrombectomy 3. Baseline NIHSS ⩾6 4. Premorbid mRS ⩽2 5. Written informed consent obtained from the patient or legally responsible person
Exclusion criteria
1. Contraindication of endovascular thrombectomy 2. Contraindication of remote ischemic conditioning, such as severe soft tissue injury, fracture, or vascular injury in the upper limb, acute or subacute venous thrombosis, arterial occlusive disease, and subclavian steal syndrome 3. Head CT showing cerebral hernia and midline displacement 4. Pregnancy or lactation 5. Previous remote ischemic conditioning therapy or similar treatment 6. Severe hepatic and renal dysfunction 7. Life expectancy of less than 3 months or inability to complete the study for other reasons 8. Unwilling to be followed up or poor compliance 9. Current or past participation in other clinical research, or participation in this study within 3 months prior to admission 10. Other conditions that the researchers think make the patient unsuitable for the study

CT: computed tomography; CTA: computed tomography angiography; DSA: digital subtraction angiography; NIHSS: National Institutes of Health Stroke Scale; mRS: modified Rankin Scale.

Randomization

Participants will be randomized in a 1:1 ratio to the RIC or sham-RIC groups following a computer-generated block randomization sequence stratified by each study center. The block sizes will randomly vary between 4, 6, and 8. Random numbers will be stored in opaque envelopes. Randomized envelopes will be assigned to each center in advance. Each patient will provide written informed consent in the center and receive a random treatment number based on the chronological enrollment order. Treatment allocation will be determined based on the envelope’s randomization results, which are blinded to the outcome observers.

RIC procedure

RIC will be performed on the upper arm of the unaffected side using an automatic device (BB-RIC-D5/LAPUL Medical Devices Co., Ltd, Beijing, China) with an inflation pressure of 200 mmHg (RIC group) or 60 mmHg (sham-RIC group) during ischemia. Patients will undergo RIC after EVT. During the preparation stage of this experiment, it was determined the device should be programmed to run automatically for 40 min (ischemia for 5 min, reperfusion for 5 min, and repeat for four cycles) after starting up. Participants will receive RIC twice daily for seven consecutive days from the first day of hospitalization.

During the administration of RIC, nurses will assist in performing RIC intervention and recording the local changes in skin appearance on the upper arm. Depending on the patient’s condition, the numeric rating scale (scale range, 0–10, with 0 indicating no pain and 10 indicating maximum pain) will be used to evaluate discomfort and pain. Standard medical treatment in both groups will follow the Chinese guidelines for the diagnosis and treatment of acute ischemic stroke (2018). ²

Outcomes

The primary outcome is the proportion of patients with an mRS score of 0–2 on day 90. The National Institutes of Health Stroke Scale (NIHSS), Barthel Index, and mRS scores at 24 h, 7 days, 30 ± 3 days, and 90 ± 3 days post-EVT will be used as secondary outcome measures. Secondary outcome measures also include the recanalization rate, expanded Thrombolysis in Cerebral Infarction score (eTICI score, ranges from 0 (no reperfusion) to 3 (full reperfusion in the distribution of the occluded artery)), and rate of symptomatic intracranial hemorrhage post-EVT. Mortality and all adverse events, including skin changes and pain scores, within the first 90 days will be used as safety outcome measures.

Outcome measures will be monitored at baseline, 24 h, 7 days, 30 days, and 90 days. One to two professional clinical observers in each center will perform face-to-face visits at baseline, 24 h, and 7 days. Professionally qualified observers from our stroke center will conduct all participants’ follow-ups at 30 ± 3 days and 90 ± 3 days by phone call or video call. To maintain anonymity, all observers will be unaware of the patients’ assignments or treatments.

Data Monitoring and Safety Committee

An independent Data Monitoring and Safety Committee (DMSC) has been established to ensure patient safety. The DMSC supervises the progress and data collection of the trial, primarily focusing on the feasibility and safety of the RIC procedure in every center.

Sample size estimates

In a previous study, the proportion of patients with favorable functional outcomes at 90 days (mRS ⩽2) in the thrombectomy-alone group was 36.4% (36.8% in the combined intravenous alteplase and EVT group). ¹⁵ Another meta-analysis showed that 46% of patients who received EVT plus intravenous alteplase treatment achieved functional independence at 90 days (mRS ⩽2). ¹ Based on the aforementioned studies, we estimate that 41% of patients with AIS who undergo EVT therapy will have favorable functional outcomes at 90 days. However, in an exploratory study that assessed the safety and feasibility of RIC for AIS patients undergoing EVT, 55% of subjects (11/20) achieved functional independence (mRS ⩽2). ¹³ Consequently, we estimate a 14% difference in functional independence (mRS ⩽2) between RIC and control groups. Considering a significance level of 5% and power of 80%, we computed a sample size of 398 patients (199 per group). We have accounted for a one-fifth of patients might be lost to follow-up; therefore, 498 patients (249 per group) will be recruited.

Data analysis

We will use the intention-to-treat analysis set in all randomized patients for efficacy analyses. The safety analysis set, which includes patients who receive at least one RIC, will be used for the safety analyses. Continuous variables with normal distribution will be represented as mean value ± standard deviation, whereas the median and quartile will represent continuous variables with a non-normal distribution. Categorical variables will be presented as frequencies and percentages. Multiple imputations will be used to identify the missing values of the baseline variables.

The primary outcome, which is a categorical variable, will be analyzed using an unadjusted logistic regression analysis. A multivariable model will be used to conduct a secondary analysis of the primary outcome, which will include age, baseline NIHSS, mRS score before stroke, and stroke onset-to-treatment time. With the inclusion of multiplicative interaction factors, subgroup analyses will be conducted to assess the effect modification (heterogeneity of the treatment effect).

Secondary outcomes will be analyzed using linear or logistic regression models (binary or ordinal regression as appropriate) with the same adjustment as the primary outcome. SPSS 19.0 software will be used for statistical data analysis. Statistical significance was set at P < 0.05.

Current status

This study was registered on 13 July 2021. The first patient was enrolled on 26 August 2021, and all study sites are still recruiting the participants. At the time of the first submission of this article, the DMSC has been established and 92 patients have been recruited into SERIC-EVT. Recruitment will continue until the complete sample size is achieved.