Rapid Local Ischemic Postconditioning on Stroke After Thrombectomy (RAPIDIMPROVE)

Rapid Local Ischemic Postconditioning Following Successful Recanalization After Endovascular Thrombectomy in Large Ischemic Core Stroke

The main goal of this study is to find out if a new, quick "brain rescue" procedure can help people recover better from a severe stroke caused by a large vessel occlusion.

When someone has this type of stroke, doctors often perform a procedure called an endovascular thrombectomy (EVT). In EVT, they thread a thin tube through a blood vessel up to the brain to remove the clot and restore blood flow. This is a highly effective treatment.

However, for some patients, suddenly restoring blood flow can cause additional, unexpected injury to the brain. This is called "reperfusion injury." This study tests a technique called rapid local ischemic postconditioning (RL-IPostC) that might prevent this extra damage. It's a very simple additional step performed immediately after the clot is successfully removed.

The doctor would briefly inflate and deflate a tiny balloon inside the proximal brain artery after recanalization, creating very short, controlled "pauses" in blood flow. This is believed to give brain cells a gentler "wake-up" call, helping them tolerate the return of oxygen-rich blood.

The study will test two different "doses" of this procedure (meaning different numbers of inflation/deflation cycles) against the standard care (no additional procedure).

Phase IIb (the first part): Which dose of RL-IPostC (high or low) is more promising for reducing early brain swelling (measured by whether the brain's midline has shifted less than 3 mm on a 24-hour scan)? Phase III (the main part): Using the best dose from Phase IIb, does RL-IPostC improve a patient's functional recovery three months later, specifically enabling them to walk and manage daily activities without help? A total of 288 participants who have had a large-vessel occlusion stroke and successful clot removal will be enrolled. If early results look promising but not quite conclusive, the study can increase the total number of participants up to 448 to get a clearer answer.

If successful, this study could identify a simple, low-cost add-on procedure to a standard stroke treatment that improves long-term recovery and quality of life for thousands of stroke patients. It's a potential new tool to protect the brain after blood flow is restored. This is a carefully designed study testing a gentle "on/off" blood flow technique right after clot removal, to see if it can reduce brain injury and help people walk and live more independently after a severe stroke.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Procedure: High-dose RL-IPostC; Procedure: Low-dose RL-IPostC

Detailed Description

RAPID IMPROVE is a seamless design which integrates dose selection (Phase IIb) and confirmatory testing (Phase III) into a single continuous trial. This approach preserves study power, controls the overall type I error rate, and accelerates the evaluation of rapid local ischemic postconditioning (RL-IPostC) in patients with acute anterior circulation large-core ischemic stroke who achieve successful recanalization defined as modified Thrombolysis In Cerebral Infarction (mTICI) 2b/3 after mechanical thrombectomy.

Randomization is performed centrally using a web-based system immediately after confirmation of successful recanalization. In Phase IIb, eligible patients are allocated 1:1:1 to high-dose RL-IPostC, low-dose RL-IPostC, or control (no postconditioning). After the dose selection decision at the end of Phase IIb, Phase III continues with a 1:1 randomization between the selected dose and control. Randomization is stratified by study site and baseline NIHSS score (<17 vs. ≥17) to ensure balance of prognostic factors.

The treating interventionalist cannot be blinded due to the nature of the postconditioning procedure. However, all outcome assessors - including the investigators who perform follow-up mRS assessments, the imaging core laboratory personnel, and the clinical events committee - are blinded to treatment assignment. The Data Safety Monitoring Board (DSMB) has access to unblinded data for safety monitoring. An imaging core laboratory centrally evaluates all baseline and follow-up CT, CTA, CTP, MRI, and DSA images. Separate analysts interpret baseline eligibility images (ASPECTS, core volume) and post-procedure images (midline shift, infarct volume, net water uptake, CSF/ICV ratio), all blinded to treatment allocation.

RL-IPostC is performed using a balloon guide catheter (BGC) positioned at the C1-C2 segment of the ipsilateral internal carotid artery, carefully avoiding the carotid sinus. The intervention should be initiated as soon as possible after confirmation of successful recanalization, and no later than 5 minutes. All patients receive standard post-thrombectomy care in a stroke unit, including a mandatory repeat CT scan at 24 hours. Antithrombotic or antiplatelet therapy is given according to local clinical practice and is recorded.

The trial uses a 3-arm, 2-stage multi-arm multi-stage (MAMS) design. The primary endpoint for stage 1 (Phase IIb) is the absence of midline shift (>3 mm at the level of the septum pellucidum) on 24 hours imaging (non-contrast computed tomography or magnetic resonance imaging). Based on the research team's cohort study, the control arm response rate (absence of midline shift) is assumed to be 40%, with an absolute improvement of 30% for an effective dose. One-sided α = 0.10, power = 95%.

The primary endpoint for stage 2 (Phase III) is the proportion of patients with mRS 0-3 at 90 days post-procedure. The control arm response rate is assumed to be 40% (derived from SELECT2 trial results), with an absolute improvement of 20% for the selected dose. One-sided α = 0.025, power = 85%.

Overall family-wise error rate (FWER) is controlled at one-sided 0.045. The overall pairwise α is 0.025 (one-sided) and the overall pairwise power is 80.7%. A positive predictive value (probability of mRS 0-3 given absence of midline shift) is prespecified as 0.36 for control and 0.60 for treatment, based on the same cohort study, to appropriately link the two stages.

Sample size was calculated using the nstagebin function (version 1.0.2) in Stata. The maximum planned sample size is 288 patients assuming 10% dropout across both stages. Stage 1 (Phase IIb) requires 48 patients per arm (144 total). Stage 2 (Phase III) adds 72 patients per arm (144 total for two arms), accumulating to 120 evaluable patients per arm for the selected dose and control.

An adaptive sample size increase is permitted in Phase III. At Interim Analysis #3 (84 patients enrolled per arm in Phase III, i.e., 168 patients), a blinded statistician will calculate the conditional power for the primary endpoint (mRS 0-3) using the method of Mehta and Pocock. If the conditional power falls within a prespecified "promising" range, the sample size may be increased up to a maximum of 200 patients per arm in Phase III, with the goal of raising conditional power to 0.80. The total sample size including this adaptation is capped at 448 patients (200 per arm in Phase III plus the non-selected arm patients from Phase IIb).

Three protocol-specified interim analyses are scheduled:

IA1 (72 patients, 24 per arm): early safety review. IA2 (144 patients, 48 per arm): end of Phase IIb - dose selection and safety assessment.

IA3 (216 patients: 84 control, 84 selected intervention, 48 from the non-selected arm): conditional power for sample size re-estimation.

Safety stopping rules follow a two-step frequentist confidence approach for symptomatic intracranial hemorrhage (sICH) and 3-month mortality.

For sICH:

Step 1 - If the confidence that the sICH rate in an intervention arm exceeds 20% is >90%, proceed to Step 2.

Step 2 - If the confidence that the excess sICH rate over the control arm is ≥5% exceeds 90%, enrollment is placed on hold and the DSMB convenes to determine continuation.

For mortality:

Step 1 - Threshold 40% (confidence >90%). Step 2 - Excess over control ≥10% (confidence >90%).

Dose selection rules at end of Phase IIb (efficacy boundary p < 0.1, one-sided, for the imaging endpoint):

Only low dose crosses boundary → select low dose. Only high dose crosses boundary → select high dose. Both doses cross → select the dose with lower 3-month mortality. Neither cross → pause enrollment; DSMB meets to discuss possible trial termination.

A clinical events committee of three independent experts adjudicates all complications, including sICH (using the SITS-MOST definition: parenchymal hematoma type 2 with an NIHSS worsening of ≥ 4 points compared to the pre-deterioration assessment) and other serious adverse events.

• Study Type: Interventional
• Enrollment (Estimated): 448
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yining Tao, MD; Phone Number: 0086-021-64844183; Email: yiningtao1001@163.com
• Study Contact Backup: Name: Jiangshan Deng, MD; Phone Number: 0086-021-64507181; Email: johnson120@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-85 years
2. Diagnosis of acute ischemic stroke
3. Pre-stroke mRS 0-1
4. Baseline NIHSS score ≥ 6
5. Time from symptom onset to start of endovascular procedure (puncture) < 24 hours; onset time defined as "last known well" time
6. Imaging criteria: ASPECTS 3-5 on CT, or ASPECTS > 5 with acute ischemic core volume (defined as rCBF < 30% or ADC < 620) ≥ 50 mL
7. Occlusion of the intracranial segment of the internal carotid artery or the middle cerebral artery (M1/M2), confirmed as the symptomatic culprit vessel
8. After thrombectomy, the culprit vessel is considered to be occluded by an embolus, and successful recanalization (mTICI 2b/3, i.e., ≥ 50% perfusion) is achieved
9. Written informed consent signed by the patient or a legal representative

Exclusion Criteria:

1. Presence of stenosis (≥ 50%) in the ipsilateral middle cerebral artery, internal carotid artery, or common carotid artery proximal to the occlusion site
2. Multiple emboli across different circulations (simultaneous anterior and posterior circulation emboli, or simultaneous left and right anterior circulation emboli)
3. Evidence on CT of extensive cerebral edema, midline shift, significant mass effect, or signs of brain herniation
4. Presence of a life-threatening disease with a prognosis < 6 months, making 3-month follow-up impossible
5. Severe psychiatric disorder or heart failure
6. Concurrent participation in another clinical drug or device study
7. Any other condition that, in the investigator's judgment, makes the subject unsuitable for this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High-dose RL-IPostC; Postconditioning intervention with 2 minutes of inflation / 2 minutes of deflation, for 4 cycles.	Procedure: High-dose RL-IPostC; For acute anterior circulation with large core ischemic stroke patients who achieve successful vessel recanalization (mTICI 2b/3) after thrombectomy, within 5 minutes, the balloon guide catheter (BGC) is positioned in the straight segment of the ipsilateral internal carotid artery at the C1-C2 level, avoiding the carotid sinus. Repetitive balloon inflations (2 minutes) to block blood flow followed by deflations (2 minutes) to restore blood flow (for 4 cycles) are performed. After the first BGC inflation, confirmation of antegrade flow blockade in the internal carotid artery is required. At the end of the cycle, angiography is performed to confirm vessel patency.
Experimental: Low-dose RL-IPostC; Postconditioning intervention with 15 seconds of inflation / 15 seconds of deflation, for 5 cycles.	Procedure: Low-dose RL-IPostC; For acute anterior circulation with large core ischemic stroke patients who achieve successful vessel recanalization (mTICI 2b/3) after thrombectomy, within 5 minutes, the balloon guide catheter (BGC) is positioned in the straight segment of the ipsilateral internal carotid artery at the C1-C2 level, avoiding the carotid sinus. Repetitive balloon inflations (15 seconds) to block blood flow followed by deflations (15 seconds) to restore blood flow (for 5 cycles) are performed. After the first BGC inflation, confirmation of antegrade flow blockade in the internal carotid artery is required. At the end of the cycle, angiography is performed to confirm vessel patency.
No Intervention: Control; No postconditioning intervention after successful thrombectomy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase III: Proportion of subjects with mRS 0-3 at 90 days.	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	90 ± 7 days post-procedure
Phase IIb: proportion of subjects without midline shift ( >3mm)	Midline shift was measured at the level of the translucent septum in the follow-up NCCT or MRI at 24 hours.	24 ± 6 hours after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects with good outcome (mRS 0-2) at 90 days	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	90 ± 7 days post-procedure
Distribution of mRS at 90 days	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	90 ± 7 days post-procedure
Proportion of subjects with mRS 0-3 at 1 year	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	1 year ± 15 days post-procedure.
Proportion of subjects with mRS 0-2 at 1 year	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	1 year ± 15 days post-procedure.
Distribution of mRS at 1 year.	The modified Rankin Scale (mRS) is a single-item, global outcome rating scale used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other neurological disorders. The mRS is a 7-level ordinal scale ranging from 0 to 6, where higher scores indicate greater disability. 0-No symptoms at all; No significant disability despite symptoms: able to carry out all usual duties and activities; Slight disability：unable to carry out all previous activities but able to look after own affairs without assistance; Moderate disability：require some help, but able to walk without assistance; Moderate severe disability：unable to walk without assistance, and unable to attend to own bodily needs without assistance; Severe disability：bedridden, incontinent, and require constant nursing care and attention; Death	1 year ± 15 days post-procedure.
Change in NIHSS score between day 5-7 or discharge	The National Institutes of Health Stroke Scale (NIHSS) is a systematic, quantitative clinical assessment tool used to evaluate and document neurological deficits in patients with stroke. The scale is a 15-item neurological examination that evaluates the effect of an acute stroke. Each item is scored on a 3- to 5-point ordinal scale, with '0' typically indicating normal function. The total score ranges from 0 to 42, with higher scores indicating more severe neurological impairment.	Day 5-7 post-procedure.
EQ-5D-5L score at 90 days	The EQ-5D-5L is a standardized generic measure of health-related quality of life, developed by the EuroQol Group. It comprises a descriptive system with five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each rated on five severity levels (no problems to extreme problems), generating 3,125 possible health states. An EQ visual analogue scale (0-100) records self-rated health. The five-digit profile converts to a utility index using population value sets, enabling quality-adjusted life-year calculation for cost-effectiveness analyses.	90 ± 7 days post-procedure
EQ-5D-5L score at 1 year	The EQ-5D-5L is a standardized generic measure of health-related quality of life, developed by the EuroQol Group. It comprises a descriptive system with five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each rated on five severity levels (no problems to extreme problems), generating 3,125 possible health states. An EQ visual analogue scale (0-100) records self-rated health. The five-digit profile converts to a utility index using population value sets, enabling quality-adjusted life-year calculation for cost-effectiveness analyses.	1 year ± 15 days post-procedure.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infarct volume at 24-72 hours post-randomization	Infarction based on DWI hyperintensity, if MRI unavailable, based on hypodensity on CT	24-72 hours post-randomization
Ratio of increase in infarct volume at 24-72 hours post-randomization compared to baseline infarct volume	Baseline core infarct defined as rCBF < 30% or ADC < 620. Infarction at 24-72 hours post-randomization is defined on DWI hyperintensity, if MRI unavailable, based on hypodensity on CT.	24-72 hours post-randomization
Change in net water uptake between 24-72 hours post-randomization and pre-procedure	Net water uptake (NWU) was quantified in early infarct at the time of admission and 24-72 hours follow-up CT imaging. The early hypoattenuate infarct core or mapping core lesion from CTP or NCCT was assessed by densitometric measurements (D ischemic). A mirrored region of interest (ROI) was placed within normal tissue of the contralateral hemisphere (D normal). Quantitative NWU was then calculated as NWU=1-(D ischemic/D normal). Subsequently, change in net water uptake was calculated as the difference in NWU between the follow-up NCCT and admission NCCT.	24-72 hours post-randomization
Change in CSF/intracranial volume ratio (∆CSF/ICV) between 24-72 hours post-randomization and pre-procedure.	Intracranial CSF volumes were obtained using an established work flow which included CT image normalization and brain extraction, registration of baseline CT to supratentorial brain mask, coregistration of follow-up CT to baseline supratentorial mask, and segmentation of CSF regions (sulci and ventricles) from cerebral hemispheres, after excluding any visibly infarcted tissue. Segmented CSF was divided into hemispheric volumes using the midlines from each registered slice. The hemispheric CSF ratio was calculated as the CSF volume in the stroke-affected hemisphere divided by the volume in the contralateral hemisphere. Intracranial volume (ICV) was calculated by measuring the total supratentorial region registered between serial CT scans. The CSF volume, hemispheric CSF ratio, and CSF/ICV ratio were recorded in both the follow-up CT and the admission CT. Changes in CSF volume (ΔCSF) and the ratio of CSF volume to ICV (∆CSF/ICV) from baseline to follow-up CT were also calculated.	24-72 hours post-randomization
Overall mortality within 3 months.	Overall mortality within 3 months post-randomization.	3 months post-randomization
Symptomatic intracranial hemorrhage (sICH) at 24-72 hours	According to SITS-MOST definition: parenchymal hematoma type 2 (PH2) with an NIHSS worsening of ≥ 4 points compared to before the neurological deterioration, not to baseline.	24-72 hours post-randomization

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University Affiliated Sixth People's Hospital
• Investigators: Principal Investigator: Yueqi Zhu, MD, Shanghai Jiao Tong University Affiliated Sixth People's Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): May 30, 2028
• Study Completion (Estimated): May 30, 2029

Study Registration Dates

• First Submitted: May 14, 2026
• First Submitted That Met QC Criteria: May 14, 2026
• First Posted (Actual): May 20, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 21, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Ischemic reperfusion injury; Neuroprotection; Ischemic postconditioning; Endovascular thrombectomy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: RAPID IMPROVE-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No